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<!DOCTYPE html> <html lang="en" class="no-js"> <head> <meta charset="UTF-8"> <meta http-equiv="X-UA-Compatible" content="IE=edge"> <meta name="applicable-device" content="pc,mobile"> <meta name="viewport" content="width=device-width, initial-scale=1"> <meta name="robots" content="max-image-preview:large"> <meta name="access" content="Yes"> <meta name="360-site-verification" content="1268d79b5e96aecf3ff2a7dac04ad990" /> <title>Single-cell transcriptomic and neuropathologic analysis reveals dysregulation of the integrated stress response in progressive supranuclear palsy | Acta Neuropathologica </title> <meta name="twitter:site" content="@SpringerLink"/> <meta name="twitter:card" content="summary_large_image"/> <meta name="twitter:image:alt" content="Content cover image"/> <meta name="twitter:title" content="Single-cell transcriptomic and neuropathologic analysis reveals dysregulation of the integrated stress response in progressive supranuclear palsy"/> <meta name="twitter:description" content="Acta Neuropathologica - Progressive supranuclear palsy (PSP) is a sporadic neurodegenerative tauopathy variably affecting brainstem and cortical structures, and characterized by tau inclusions in..."/> <meta name="twitter:image" content="https://static-content.springer.com/image/art%3A10.1007%2Fs00401-024-02823-w/MediaObjects/401_2024_2823_Fig1_HTML.png"/> <meta name="journal_id" content="401"/> <meta name="dc.title" content="Single-cell transcriptomic and neuropathologic analysis reveals dysregulation of the integrated stress response in progressive supranuclear palsy"/> <meta name="dc.source" content="Acta Neuropathologica 2024 148:1"/> <meta name="dc.format" content="text/html"/> <meta name="dc.publisher" content="Springer"/> <meta name="dc.date" content="2024-12-09"/> <meta name="dc.type" content="OriginalPaper"/> <meta name="dc.language" content="En"/> <meta name="dc.copyright" content="2024 The Author(s)"/> <meta name="dc.rights" content="2024 The Author(s)"/> <meta name="dc.rightsAgent" content="journalpermissions@springernature.com"/> <meta name="dc.description" content="Progressive supranuclear palsy (PSP) is a sporadic neurodegenerative tauopathy variably affecting brainstem and cortical structures, and characterized by tau inclusions in neurons and glia. The precise mechanism whereby these protein aggregates lead to cell death remains unclear. To investigate the contribution of these different cellular abnormalities to PSP pathogenesis, we performed single-nucleus RNA sequencing (snRNA-seq) and analyzed 50,708 high quality nuclei targeting the diencephalon, including the subthalamic nucleus and adjacent structures, from human post-mortem PSP brains with varying degrees of pathology compared to controls. Cell-type-specific differential expression and pathway analysis identified both common and discrete changes in numerous pathways previously implicated in PSP and other neurodegenerative disorders. This included EIF2 signaling, an adaptive pathway activated in response to diverse stressors, which was activated in multiple vulnerable cell types and validated in independent snRNA-seq and bulk RNA-seq datasets. Using immunohistochemistry, we found that activated eIF2α was positively correlated with tau pathology burden in vulnerable brain regions. Multiplex immunofluorescence localized activated eIF2α positivity to hyperphosphorylated tau (p-tau) positive neurons and ALDH1L1-positive astrocytes, supporting the increased transcriptomic EIF2 activation observed in these vulnerable cell types. In conclusion, these data provide insights into cell-type-specific pathological changes in PSP and support the hypothesis that failure of adaptive stress pathways play a mechanistic role in the pathogenesis and progression of PSP."/> <meta name="prism.issn" content="1432-0533"/> <meta name="prism.publicationName" content="Acta Neuropathologica"/> <meta name="prism.publicationDate" content="2024-12-09"/> <meta name="prism.volume" content="148"/> <meta name="prism.number" content="1"/> <meta name="prism.section" content="OriginalPaper"/> <meta name="prism.startingPage" content="1"/> <meta name="prism.endingPage" content="22"/> <meta name="prism.copyright" content="2024 The Author(s)"/> <meta name="prism.rightsAgent" content="journalpermissions@springernature.com"/> <meta name="prism.url" content="https://link.springer.com/article/10.1007/s00401-024-02823-w"/> <meta name="prism.doi" content="doi:10.1007/s00401-024-02823-w"/> <meta name="citation_pdf_url" content="https://link.springer.com/content/pdf/10.1007/s00401-024-02823-w.pdf"/> <meta name="citation_fulltext_html_url" content="https://link.springer.com/article/10.1007/s00401-024-02823-w"/> <meta name="citation_journal_title" content="Acta Neuropathologica"/> <meta name="citation_journal_abbrev" content="Acta Neuropathol"/> <meta name="citation_publisher" content="Springer Berlin Heidelberg"/> <meta name="citation_issn" content="1432-0533"/> <meta name="citation_title" content="Single-cell transcriptomic and neuropathologic analysis reveals dysregulation of the integrated stress response in progressive supranuclear palsy"/> <meta name="citation_volume" content="148"/> <meta name="citation_issue" content="1"/> <meta name="citation_publication_date" content="2024/12"/> <meta name="citation_online_date" content="2024/12/09"/> <meta name="citation_firstpage" content="1"/> <meta name="citation_lastpage" content="22"/> <meta name="citation_article_type" content="Original Paper"/> <meta name="citation_fulltext_world_readable" content=""/> <meta name="citation_language" content="en"/> <meta name="dc.identifier" content="doi:10.1007/s00401-024-02823-w"/> <meta name="DOI" content="10.1007/s00401-024-02823-w"/> <meta name="size" content="502161"/> <meta name="citation_doi" content="10.1007/s00401-024-02823-w"/> <meta name="citation_springer_api_url" content="http://api.springer.com/xmldata/jats?q=doi:10.1007/s00401-024-02823-w&api_key="/> <meta name="description" content="Progressive supranuclear palsy (PSP) is a sporadic neurodegenerative tauopathy variably affecting brainstem and cortical structures, and characterized by t"/> <meta name="dc.creator" content="Whitney, Kristen"/> <meta name="dc.creator" content="Song, Won-Min"/> <meta name="dc.creator" content="Sharma, Abhijeet"/> <meta name="dc.creator" content="Dangoor, Diana K."/> <meta name="dc.creator" content="Farrell, Kurt"/> <meta name="dc.creator" content="Krassner, Margaret M."/> <meta name="dc.creator" content="Ressler, Hadley W."/> <meta name="dc.creator" content="Christie, Thomas D."/> <meta name="dc.creator" content="Kandoi, Shrishtee"/> <meta name="dc.creator" content="Walker, Ruth H."/> <meta name="dc.creator" content="Nirenberg, Melissa J."/> <meta name="dc.creator" content="Frucht, Steven J."/> <meta name="dc.creator" content="Riboldi, Giulietta M."/> <meta name="dc.creator" content="Zhang, Bin"/> <meta name="dc.creator" content="Pereira, Ana C."/> <meta name="dc.creator" content="Crary, John F."/> <meta name="dc.subject" content="Pathology"/> <meta name="dc.subject" content="Neurosciences"/> <meta name="citation_reference" content="citation_journal_title=J Neurosci; citation_title=Tau accumulation activates the unfolded protein response by impairing endoplasmic reticulum-associated degradation; citation_author=JF Abisambra, UK Jinwal, LJ Blair, JC O'Leary, Q Li, S Brady, L Wang, CE Guidi, B Zhang, BA Nordhues; citation_volume=33; citation_publication_date=2013; citation_pages=9498-9507; citation_doi=10.1523/JNEUROSCI.5397-12.2013; citation_id=CR1"/> <meta name="citation_reference" content="citation_journal_title=Acta Neuropathol; citation_title=Globular glial tauopathies (GGT): consensus recommendations; citation_author=Z Ahmed, EH Bigio, H Budka, DW Dickson, I Ferrer, B Ghetti, G Giaccone, KJ Hatanpaa, JL Holton, KA Josephs; citation_volume=126; citation_publication_date=2013; citation_pages=537-544; citation_doi=10.1007/s00401-013-1171-0; citation_id=CR2"/> <meta name="citation_reference" content="citation_journal_title=Cell Death Dis; citation_title=ER stress and UPR in Alzheimer's disease: mechanisms, pathogenesis, treatments; citation_author=A Ajoolabady, D Lindholm, J Ren, D Pratico; citation_volume=13; citation_publication_date=2022; citation_pages=706; citation_doi=10.1038/s41419-022-05153-5; citation_id=CR3"/> <meta name="citation_reference" content="citation_journal_title=Acta Neuropathol Commun; citation_title=Single-nucleus RNA-seq identifies Huntington disease astrocyte states; citation_author=O Al-Dalahmah, AA Sosunov, A Shaik, K Ofori, Y Liu, JP Vonsattel, I Adorjan, V Menon, JE Goldman; citation_volume=8; citation_publication_date=2020; citation_pages=19; citation_doi=10.1186/s40478-020-0880-6; citation_id=CR4"/> <meta name="citation_reference" content="citation_journal_title=Brain Pathol; citation_title=Staging of neurofibrillary pathology in Alzheimer's disease: a study of the BrainNet Europe consortium; citation_author=I Alafuzoff, T Arzberger, S Al-Sarraj, I Bodi, N Bogdanovic, H Braak, O Bugiani, K Del-Tredici, I Ferrer, E Gelpi; citation_volume=18; citation_publication_date=2008; citation_pages=484-496; citation_doi=10.1111/j.1750-3639.2008.00147.x; citation_id=CR5"/> <meta name="citation_reference" content="citation_journal_title=Acta Neuropathol; citation_title=Gene expression, methylation and neuropathology correlations at progressive supranuclear palsy risk loci; citation_author=M Allen, JD Burgess, T Ballard, D Serie, X Wang, CS Younkin, Z Sun, N Kouri, S Baheti, C Wang; citation_volume=132; citation_publication_date=2016; citation_pages=197-211; citation_doi=10.1007/s00401-016-1576-7; citation_id=CR6"/> <meta name="citation_reference" content="citation_journal_title=Acta Neuropathol; citation_title=Divergent brain gene expression patterns associate with distinct cell-specific tau neuropathology traits in progressive supranuclear palsy; citation_author=M Allen, X Wang, DJ Serie, SL Strickland, JD Burgess, S Koga, CS Younkin, TT Nguyen, KG Malphrus, SJ Lincoln; citation_volume=136; citation_publication_date=2018; citation_pages=709-727; citation_doi=10.1007/s00401-018-1900-5; citation_id=CR7"/> <meta name="citation_reference" content="Andrews S (2010) FastQC: a quality control tool for high throughput sequence data http://www.bioinformatics.babraham.ac.uk/projects/fastqc "/> <meta name="citation_reference" content="citation_journal_title=Nat Immunol; citation_title=Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage; citation_author=D Aran, AP Looney, L Liu, E Wu, V Fong, A Hsu, S Chak, RP Naikawadi, PJ Wolters, AR Abate; citation_volume=20; citation_publication_date=2019; citation_pages=163-172; citation_doi=10.1038/s41590-018-0276-y; citation_id=CR9"/> <meta name="citation_reference" content="citation_journal_title=Acta Neuropathol Commun; citation_title=The role of DHCR24 in the pathogenesis of AD: re-cognition of the relationship between cholesterol and AD pathogenesis; citation_author=X Bai, M Mai, K Yao, M Zhang, Y Huang, W Zhang, X Guo, Y Xu, Y Zhang, A Qurban; citation_volume=10; citation_publication_date=2022; citation_pages=35; citation_doi=10.1186/s40478-022-01338-3; citation_id=CR10"/> <meta name="citation_reference" content="citation_journal_title=J Mol Cell Biol; citation_title=Intraneuronal tau aggregation induces the integrated stress response in astrocytes; citation_author=KL Batenburg, NN Kasri, VM Heine, W Scheper; citation_publication_date=2023; citation_doi=10.1093/jmcb/mjac071; citation_id=CR11"/> <meta name="citation_reference" content="citation_journal_title=J Biol Chem; citation_title=Phosphorylation of tau proteins to a state like that in Alzheimer's brain is catalyzed by a calcium/calmodulin-dependent kinase and modulated by phospholipids; citation_author=J Baudier, RD Cole; citation_volume=262; citation_publication_date=1987; citation_pages=17577-17583; citation_doi=10.1016/S0021-9258(18)45420-8; citation_id=CR12"/> <meta name="citation_reference" content="citation_journal_title=Trends Neurosci; citation_title=Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease; citation_author=I Bezprozvanny, MP Mattson; citation_volume=31; citation_publication_date=2008; citation_pages=454-463; citation_doi=10.1016/j.tins.2008.06.005; citation_id=CR13"/> <meta name="citation_reference" content="citation_journal_title=J Alzheimers Dis; citation_title=MTRNR2L12: A candidate blood marker of early Alzheimer's disease-like dementia in adults with down syndrome; citation_author=M Bik-Multanowski, JJ Pietrzyk, A Midro; citation_volume=46; citation_publication_date=2015; citation_pages=145-150; citation_doi=10.3233/JAD-143030; citation_id=CR14"/> <meta name="citation_reference" content="citation_journal_title=Bioinformatics; citation_title=Trimmomatic: a flexible trimmer for Illumina sequence data; citation_author=AM Bolger, M Lohse, B Usadel; citation_volume=30; citation_publication_date=2014; citation_pages=2114-2120; citation_doi=10.1093/bioinformatics/btu170; citation_id=CR15"/> <meta name="citation_reference" content="citation_journal_title=Lancet Neurol; citation_title=Advances in progressive supranuclear palsy: new diagnostic criteria, biomarkers, and therapeutic approaches; citation_author=AL Boxer, JT Yu, LI Golbe, I Litvan, AE Lang, GU Hoglinger; citation_volume=16; citation_publication_date=2017; citation_pages=552-563; citation_doi=10.1016/S1474-4422(17)30157-6; citation_id=CR16"/> <meta name="citation_reference" content="citation_journal_title=Angiogenesis; citation_title=Regulation of angiogenesis and endothelial cell function by connective tissue growth factor (CTGF) and cysteine-rich 61 (CYR61); citation_author=DR Brigstock; citation_volume=5; citation_publication_date=2002; citation_pages=153-165; citation_doi=10.1023/a:1023823803510; citation_id=CR17"/> <meta name="citation_reference" content="citation_journal_title=Dev Neurobiol; citation_title=Increased apoptosis during neonatal brain development underlies the adult behavioral deficits seen in mice lacking a functional paternally expressed gene 3 (Peg3); citation_author=KD Broad, JP Curley, EB Keverne; citation_volume=69; citation_publication_date=2009; citation_pages=314-325; citation_doi=10.1002/dneu.20702; citation_id=CR18"/> <meta name="citation_reference" content="citation_journal_title=EMBO Mol Med; citation_title=PERK activation mitigates tau pathology in vitro and in vivo; citation_author=J Bruch, H Xu, TW Rosler, A Andrade, PH Kuhn, SF Lichtenthaler, T Arzberger, KF Winklhofer, U Muller, GU Hoglinger; citation_volume=9; citation_publication_date=2017; citation_pages=371-384; citation_doi=10.15252/emmm.201606664; citation_id=CR19"/> <meta name="citation_reference" content="citation_journal_title=Mol Neurodegener; citation_title=Joint genome-wide association study of progressive supranuclear palsy identifies novel susceptibility loci and genetic correlation to neurodegenerative diseases; citation_author=JA Chen, Z Chen, H Won, AY Huang, JK Lowe, K Wojta, JS Yokoyama, G Bensimon, PN Leigh, C Payan; citation_volume=13; citation_publication_date=2018; citation_pages=41; citation_doi=10.1186/s13024-018-0270-8; citation_id=CR20"/> <meta name="citation_reference" content="citation_journal_title=J Neurosci; citation_title=Protein phosphatases and calcium/calmodulin-dependent protein kinase II-dependent synaptic plasticity; citation_author=RJ Colbran; citation_volume=24; citation_publication_date=2004; citation_pages=8404-8409; citation_doi=10.1523/JNEUROSCI.3602-04.2004; citation_id=CR21"/> <meta name="citation_reference" content="citation_journal_title=Science; citation_title=The integrated stress response: from mechanism to disease; citation_author=M Costa-Mattioli, P Walter; citation_publication_date=2020; citation_doi=10.1126/science.aat5314; citation_id=CR22"/> <meta name="citation_reference" content="citation_journal_title=Brain; citation_title=Alterations in the levels of iron, ferritin and other trace metals in Parkinson's disease and other neurodegenerative diseases affecting the basal ganglia; citation_author=DT Dexter, A Carayon, F Javoy-Agid, Y Agid, FR Wells, SE Daniel, AJ Lees, P Jenner, CD Marsden; citation_volume=114; citation_issue=Pt 4; citation_publication_date=1991; citation_pages=1953-1975; citation_doi=10.1093/brain/114.4.1953; citation_id=CR23"/> <meta name="citation_reference" content="citation_journal_title=Curr Opin Neurol; citation_title=Neuropathology of variants of progressive supranuclear palsy; citation_author=DW Dickson, Z Ahmed, AA Algom, Y Tsuboi, KA Josephs; citation_volume=23; citation_publication_date=2010; citation_pages=394-400; citation_doi=10.1097/WCO.0b013e32833be924; citation_id=CR24"/> <meta name="citation_reference" content="citation_journal_title=J Neuropathol Exp Neurol; citation_title=Office of rare diseases neuropathologic criteria for corticobasal degeneration; citation_author=DW Dickson, C Bergeron, SS Chin, C Duyckaerts, D Horoupian, K Ikeda, K Jellinger, PL Lantos, CF Lippa, SS Mirra; citation_volume=61; citation_publication_date=2002; citation_pages=935-946; citation_doi=10.1093/jnen/61.11.935; citation_id=CR25"/> <meta name="citation_reference" content="citation_journal_title=Brain Pathol; citation_title=Progressive supranuclear palsy: pathology and genetics; citation_author=DW Dickson, R Rademakers, ML Hutton; citation_volume=17; citation_publication_date=2007; citation_pages=74-82; citation_doi=10.1111/j.1750-3639.2007.00054.x; citation_id=CR26"/> <meta name="citation_reference" content="citation_journal_title=Bioinformatics; citation_title=STAR: ultrafast universal RNA-seq aligner; citation_author=A Dobin, CA Davis, F Schlesinger, J Drenkow, C Zaleski, S Jha, P Batut, M Chaisson, TR Gingeras; citation_volume=29; citation_publication_date=2013; citation_pages=15-21; citation_doi=10.1093/bioinformatics/bts635; citation_id=CR27"/> <meta name="citation_reference" content="citation_journal_title=Stem Cell Reports; citation_title=Distinct neurodegenerative changes in an induced pluripotent stem cell model of frontotemporal dementia linked to mutant TAU protein; citation_author=M Ehrlich, AL Hallmann, P Reinhardt, MJ Arauzo-Bravo, S Korr, A Ropke, OE Psathaki, P Ehling, SG Meuth, AL Oblak; citation_volume=5; citation_publication_date=2015; citation_pages=83-96; citation_doi=10.1016/j.stemcr.2015.06.001; citation_id=CR28"/> <meta name="citation_reference" content="citation_journal_title=Parkinsonism Relat Disord; citation_title=Neuropathological findings of PSP in the elderly without clinical PSP: possible incidental PSP?; citation_author=VG Evidente, CH Adler, MN Sabbagh, DJ Connor, JG Hentz, JN Caviness, LI Sue, TG Beach; citation_volume=17; citation_publication_date=2011; citation_pages=365-371; citation_doi=10.1016/j.parkreldis.2011.02.017; citation_id=CR29"/> <meta name="citation_reference" content="citation_journal_title=J Alzheimers Dis; citation_title=Neuronal hemoglobin is reduced in Alzheimer's disease, argyrophilic grain disease, Parkinson's disease, and dementia with Lewy bodies; citation_author=I Ferrer, A Gomez, M Carmona, G Huesa, S Porta, M Riera-Codina, M Biagioli, S Gustincich, E Aso; citation_volume=23; citation_publication_date=2011; citation_pages=537-550; citation_doi=10.3233/JAD-2010-101485; citation_id=CR30"/> <meta name="citation_reference" content="citation_journal_title=Genome Biol; citation_title=MAST: a flexible statistical framework for assessing transcriptional changes and characterizing heterogeneity in single-cell RNA sequencing data; citation_author=G Finak, A McDavid, M Yajima, J Deng, V Gersuk, AK Shalek, CK Slichter, HW Miller, MJ McElrath, M Prlic; citation_volume=16; citation_publication_date=2015; citation_pages=278; citation_doi=10.1186/s13059-015-0844-5; citation_id=CR31"/> <meta name="citation_reference" content="citation_journal_title=Radiology; citation_title=Progressive supranuclear palsy: high-field-strength MR microscopy in the human substantia nigra and globus pallidus; citation_author=P Foroutan, ME Murray, S Fujioka, KJ Schweitzer, DW Dickson, ZK Wszolek, SC Grant; citation_volume=266; citation_publication_date=2013; citation_pages=280-288; citation_doi=10.1148/radiol.12102273; citation_id=CR32"/> <meta name="citation_reference" content="citation_journal_title=Acta Neuropathol; citation_title=Cellular and regional vulnerability in frontotemporal tauopathies; citation_author=SL Forrest, JJ Kril, GM Halliday; citation_volume=138; citation_publication_date=2019; citation_pages=705-727; citation_doi=10.1007/s00401-019-02035-7; citation_id=CR33"/> <meta name="citation_reference" content="citation_journal_title=Acta Neuropathol; citation_title=Cell-specific MAPT gene expression is preserved in neuronal and glial tau cytopathologies in progressive supranuclear palsy; citation_author=SL Forrest, S Lee, N Nassir, I Martinez-Valbuena, V Sackmann, J Li, A Ahmed, MC Tartaglia, LM Ittner, AE Lang; citation_volume=146; citation_publication_date=2023; citation_pages=395-414; citation_doi=10.1007/s00401-023-02604-x; citation_id=CR34"/> <meta name="citation_reference" content="citation_journal_title=Front Neurosci; citation_title=Clusterin in Alzheimer’s disease: mechanisms, genetics, and lessons from other pathologies; citation_author=EM Foster, A Dangla-Valls, S Lovestone, EM Ribe, NJ Buckley; citation_volume=13; citation_publication_date=2019; citation_pages=164; citation_doi=10.3389/fnins.2019.00164; citation_id=CR35"/> <meta name="citation_reference" content="citation_journal_title=Parkinsonism Relat Disord; citation_title=Three sib-pairs of autopsy-confirmed progressive supranuclear palsy; citation_author=S Fujioka, MY Sanchez Contreras, AJ Strongosky, K Ogaki, NR Whaley, PM Tacik, JA Gerpen, RJ Uitti, OA Ross, ZK Wszolek; citation_volume=21; citation_publication_date=2015; citation_pages=101-105; citation_doi=10.1016/j.parkreldis.2014.10.028; citation_id=CR36"/> <meta name="citation_reference" content="citation_journal_title=Neurodegener Dis; citation_title=Familial progressive supranuclear palsy: a literature review; citation_author=S Fujioka, JA Gerpen, RJ Uitti, DW Dickson, ZK Wszolek; citation_volume=13; citation_publication_date=2014; citation_pages=180-182; citation_doi=10.1159/000354975; citation_id=CR37"/> <meta name="citation_reference" content="citation_journal_title=Brain Pathol; citation_title=Unfolded protein response activation in C9orf72 frontotemporal dementia is associated with dipeptide pathology and granulovacuolar degeneration in granule cells; citation_author=P Gami-Patel, I Dijken, LH Meeter, S Melhem, THJ Morrema, W Scheper, JC Swieten, AJM Rozemuller, AA Dijkstra, JJM Hoozemans; citation_volume=31; citation_publication_date=2021; citation_pages=163-173; citation_doi=10.1111/bpa.12894; citation_id=CR38"/> <meta name="citation_reference" content="citation_journal_title=Acta Neuropathol; citation_title=Possible neuroprotective role of clusterin in Alzheimer's disease: a quantitative immunocytochemical study; citation_author=P Giannakopoulos, E Kovari, LE French, I Viard, PR Hof, C Bouras; citation_volume=95; citation_publication_date=1998; citation_pages=387-394; citation_doi=10.1007/s004010050815; citation_id=CR39"/> <meta name="citation_reference" content="citation_journal_title=J Neurochem; citation_title=Phosphatase activity toward abnormally phosphorylated tau: decrease in Alzheimer disease brain; citation_author=CX Gong, S Shaikh, JZ Wang, T Zaidi, I Grundke-Iqbal, K Iqbal; citation_volume=65; citation_publication_date=1995; citation_pages=732-738; citation_doi=10.1046/j.1471-4159.1995.65020732.x; citation_id=CR40"/> <meta name="citation_reference" content="citation_journal_title=Fluids Barriers CNS; citation_title=Claudin-5: gatekeeper of neurological function; citation_author=C Greene, N Hanley, M Campbell; citation_volume=16; citation_publication_date=2019; citation_pages=3; citation_doi=10.1186/s12987-019-0123-z; citation_id=CR41"/> <meta name="citation_reference" content="citation_journal_title=Nat Neurosci; citation_title=A single-cell atlas of entorhinal cortex from individuals with Alzheimer's disease reveals cell-type-specific gene expression regulation; citation_author=A Grubman, G Chew, JF Ouyang, G Sun, XY Choo, C McLean, RK Simmons, S Buckberry, DB Vargas-Landin, D Poppe; citation_volume=22; citation_publication_date=2019; citation_pages=2087-2097; citation_doi=10.1038/s41593-019-0539-4; citation_id=CR42"/> <meta name="citation_reference" content="citation_journal_title=Genome Biol; citation_title=Normalization and variance stabilization of single-cell RNA-seq data using regularized negative binomial regression; citation_author=C Hafemeister, R Satija; citation_volume=20; citation_publication_date=2019; citation_pages=296; citation_doi=10.1186/s13059-019-1874-1; citation_id=CR43"/> <meta name="citation_reference" content="citation_journal_title=Aging Cell; citation_title=Neuroprotective role of gamma-enolase in microglia in a mouse model of Alzheimer's disease is regulated by cathepsin X; citation_author=A Hafner, G Glavan, N Obermajer, M Zivin, R Schliebs, J Kos; citation_volume=12; citation_publication_date=2013; citation_pages=604-614; citation_doi=10.1111/acel.12093; citation_id=CR44"/> <meta name="citation_reference" content="citation_journal_title=J Cell Biol; citation_title=Tau protein becomes long and stiff upon phosphorylation: correlation between paracrystalline structure and degree of phosphorylation; citation_author=T Hagestedt, B Lichtenberg, H Wille, EM Mandelkow, E Mandelkow; citation_volume=109; citation_publication_date=1989; citation_pages=1643-1651; citation_doi=10.1083/jcb.109.4.1643; citation_id=CR45"/> <meta name="citation_reference" content="citation_journal_title=J Neurosci Res; citation_title=Purkinje cell protein 4 positively regulates neurite outgrowth and neurotransmitter release; citation_author=S Harashima, Y Wang, T Horiuchi, Y Seino, N Inagaki; citation_volume=89; citation_publication_date=2011; citation_pages=1519-1530; citation_doi=10.1002/jnr.22688; citation_id=CR46"/> <meta name="citation_reference" content="citation_journal_title=Nat Genet; citation_title=Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease; citation_author=D Harold, R Abraham, P Hollingworth, R Sims, A Gerrish, ML Hamshere, JS Pahwa, V Moskvina, K Dowzell, A Williams; citation_volume=41; citation_publication_date=2009; citation_pages=1088-1093; citation_doi=10.1038/ng.440; citation_id=CR47"/> <meta name="citation_reference" content="citation_journal_title=Proc Natl Acad Sci U S A; citation_title=A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta; citation_author=Y Hashimoto, T Niikura, H Tajima, T Yasukawa, H Sudo, Y Ito, Y Kita, M Kawasumi, K Kouyama, M Doyu; citation_volume=98; citation_publication_date=2001; citation_pages=6336-6341; citation_doi=10.1073/pnas.101133498; citation_id=CR48"/> <meta name="citation_reference" content="citation_journal_title=Neurology; citation_title=Preliminary NINDS neuropathologic criteria for Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy); citation_author=JJ Hauw, SE Daniel, D Dickson, DS Horoupian, K Jellinger, PL Lantos, A McKee, M Tabaton, I Litvan; citation_volume=44; citation_publication_date=1994; citation_pages=2015-2019; citation_doi=10.1212/wnl.44.11.2015; citation_id=CR49"/> <meta name="citation_reference" content="citation_journal_title=Neurosci Lett; citation_title=Constant neurofibrillary changes in the neocortex in progressive supranuclear palsy. Basic differences with Alzheimer's disease and aging; citation_author=JJ Hauw, M Verny, P Delaere, P Cervera, Y He, C Duyckaerts; citation_volume=119; citation_publication_date=1990; citation_pages=182-186; citation_doi=10.1016/0304-3940(90)90829-x; citation_id=CR50"/> <meta name="citation_reference" content="citation_journal_title=Nat Rev Mol Cell Biol; citation_title=The unfolded protein response: controlling cell fate decisions under ER stress and beyond; citation_author=C Hetz; citation_volume=13; citation_publication_date=2012; citation_pages=89-102; citation_doi=10.1038/nrm3270; citation_id=CR51"/> <meta name="citation_reference" content="citation_journal_title=BMC Bioinformatics; citation_title=variancePartition: interpreting drivers of variation in complex gene expression studies; citation_author=GE Hoffman, EE Schadt; citation_volume=17; citation_publication_date=2016; citation_pages=483; citation_doi=10.1186/s12859-016-1323-z; citation_id=CR52"/> <meta name="citation_reference" content="citation_journal_title=Nat Genet; citation_title=Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy; citation_author=GU Hoglinger, NM Melhem, DW Dickson, PM Sleiman, LS Wang, L Klei, R Rademakers, R Silva, I Litvan, DE Riley; citation_volume=43; citation_publication_date=2011; citation_pages=699-705; citation_doi=10.1038/ng.859; citation_id=CR53"/> <meta name="citation_reference" content="citation_journal_title=Am J Pathol; citation_title=The unfolded protein response is activated in pretangle neurons in Alzheimer's disease hippocampus; citation_author=JJ Hoozemans, ES Haastert, DA Nijholt, AJ Rozemuller, P Eikelenboom, W Scheper; citation_volume=174; citation_publication_date=2009; citation_pages=1241-1251; citation_doi=10.2353/ajpath.2009.080814; citation_id=CR54"/> <meta name="citation_reference" content="citation_journal_title=Neurodegener Dis; citation_title=Activation of the unfolded protein response is an early event in Alzheimer's and Parkinson's disease; citation_author=JJ Hoozemans, ES Haastert, DA Nijholt, AJ Rozemuller, W Scheper; citation_volume=10; citation_publication_date=2012; citation_pages=212-215; citation_doi=10.1159/000334536; citation_id=CR55"/> <meta name="citation_reference" content="Institute B (2018) Picard tools - by broad institute https://broadinstitute.github.io/picard/ "/> <meta name="citation_reference" content="citation_journal_title=Nat Neurosci; citation_title=Single-cell genomic profiling of human dopamine neurons identifies a population that selectively degenerates in Parkinson's disease; citation_author=T Kamath, A Abdulraouf, SJ Burris, J Langlieb, V Gazestani, NM Nadaf, K Balderrama, C Vanderburg, EZ Macosko; citation_volume=25; citation_publication_date=2022; citation_pages=588-595; citation_doi=10.1038/s41593-022-01061-1; citation_id=CR57"/> <meta name="citation_reference" content="citation_journal_title=J Neural Transm Suppl; citation_title=Decreased levels of ARPP-19 and PKA in brains of down syndrome and Alzheimer's disease; citation_author=SH Kim, AC Nairn, N Cairns, G Lubec; citation_publication_date=2001; citation_doi=10.1007/978-3-7091-6262-0_21; citation_id=CR58"/> <meta name="citation_reference" content="citation_journal_title=Nat Rev Genet; citation_title=Challenges in unsupervised clustering of single-cell RNA-seq data; citation_author=VY Kiselev, TS Andrews, M Hemberg; citation_volume=20; citation_publication_date=2019; citation_pages=273-282; citation_doi=10.1038/s41576-018-0088-9; citation_id=CR59"/> <meta name="citation_reference" content="citation_journal_title=Mol Brain; citation_title=Metallothionein-3 as a multifunctional player in the control of cellular processes and diseases; citation_author=JY Koh, SJ Lee; citation_volume=13; citation_publication_date=2020; citation_pages=116; citation_doi=10.1186/s13041-020-00654-w; citation_id=CR60"/> <meta name="citation_reference" content="citation_journal_title=Nat Methods; citation_title=Fast, sensitive and accurate integration of single-cell data with Harmony; citation_author=I Korsunsky, N Millard, J Fan, K Slowikowski, F Zhang, K Wei, Y Baglaenko, M Brenner, PR Loh, S Raychaudhuri; citation_volume=16; citation_publication_date=2019; citation_pages=1289-1296; citation_doi=10.1038/s41592-019-0619-0; citation_id=CR61"/> <meta name="citation_reference" content="citation_journal_title=Acta Neuropathol; citation_title=Distribution patterns of tau pathology in progressive supranuclear palsy; citation_author=GG Kovacs, MJ Lukic, DJ Irwin, T Arzberger, G Respondek, EB Lee, D Coughlin, A Giese, M Grossman, C Kurz; citation_volume=140; citation_publication_date=2020; citation_pages=99-119; citation_doi=10.1007/s00401-020-02158-2; citation_id=CR62"/> <meta name="citation_reference" content="citation_journal_title=Bioinformatics; citation_title=Causal analysis approaches in ingenuity pathway analysis; citation_author=A Kramer, J Green, J Pollard, S Tugendreich; citation_volume=30; citation_publication_date=2014; citation_pages=523-530; citation_doi=10.1093/bioinformatics/btt703; citation_id=CR63"/> <meta name="citation_reference" content="citation_journal_title=Anim Cells Syst (Seoul); citation_title=Crosstalk between endoplasmic reticulum stress response and autophagy in human diseases; citation_author=J Kwon, J Kim, KI Kim; citation_volume=27; citation_publication_date=2023; citation_pages=29-37; citation_doi=10.1080/19768354.2023.2181217; citation_id=CR64"/> <meta name="citation_reference" content="citation_journal_title=Nat Rev Neurosci; citation_title=Calcium dyshomeostasis and intracellular signalling in Alzheimer's disease; citation_author=FM LaFerla; citation_volume=3; citation_publication_date=2002; citation_pages=862-872; citation_doi=10.1038/nrn960; citation_id=CR65"/> <meta name="citation_reference" content="citation_journal_title=Cell Biosci; citation_title=N6-methyladenosine-mediated CELF2 regulates CD44 alternative splicing affecting tumorigenesis via ERAD pathway in pancreatic cancer; citation_author=S Lai, Y Wang, T Li, Y Dong, Y Lin, L Wang, S Weng, X Zhang, C Lin; citation_volume=12; citation_publication_date=2022; citation_pages=125; citation_doi=10.1186/s13578-022-00844-0; citation_id=CR66"/> <meta name="citation_reference" content="citation_journal_title=Genome Biol; citation_title=voom: precision weights unlock linear model analysis tools for RNA-seq read counts; citation_author=CW Law, Y Chen, W Shi, GK Smyth; citation_volume=15; citation_publication_date=2014; citation_pages=R29; citation_doi=10.1186/gb-2014-15-2-r29; citation_id=CR67"/> <meta name="citation_reference" content="citation_journal_title=Ann Neurol; citation_title=Cell-specific dysregulation of iron and oxygen homeostasis as a novel pathophysiology in PSP; citation_author=S Lee, I Martinez-Valbuena, CE Andrea, M Villalba-Esparza, S Ilaalagan, B Couto, NP Visanji, AE Lang, GG Kovacs; citation_volume=93; citation_publication_date=2023; citation_pages=431-445; citation_doi=10.1002/ana.26540; citation_id=CR68"/> <meta name="citation_reference" content="citation_journal_title=Nat Neurosci; citation_title=Molecular characterization of selectively vulnerable neurons in Alzheimer's disease; citation_author=K Leng, E Li, R Eser, A Piergies, R Sit, M Tan, N Neff, SH Li, RD Rodriguez, CK Suemoto; citation_volume=24; citation_publication_date=2021; citation_pages=276-287; citation_doi=10.1038/s41593-020-00764-7; citation_id=CR69"/> <meta name="citation_reference" content="citation_journal_title=Bmc Bioinform; citation_title=RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome; citation_author=B Li, CN Dewey; citation_volume=12; citation_publication_date=2011; citation_pages=323; citation_doi=10.1186/1471-2105-12-323; citation_id=CR70"/> <meta name="citation_reference" content="citation_journal_title=Bioinformatics; citation_title=featureCounts: an efficient general purpose program for assigning sequence reads to genomic features; citation_author=Y Liao, GK Smyth, W Shi; citation_volume=30; citation_publication_date=2014; citation_pages=923-930; citation_doi=10.1093/bioinformatics/btt656; citation_id=CR71"/> <meta name="citation_reference" content="citation_journal_title=Cell Syst; citation_title=The molecular signatures database (MSigDB) hallmark gene set collection; citation_author=A Liberzon, C Birger, H Thorvaldsdottir, M Ghandi, JP Mesirov, P Tamayo; citation_volume=1; citation_publication_date=2015; citation_pages=417-425; citation_doi=10.1016/j.cels.2015.12.004; citation_id=CR72"/> <meta name="citation_reference" content="citation_journal_title=J Neuropathol Exp Neurol; citation_title=Validity and reliability of the preliminary NINDS neuropathologic criteria for progressive supranuclear palsy and related disorders; citation_author=I Litvan, JJ Hauw, JJ Bartko, PL Lantos, SE Daniel, DS Horoupian, A McKee, D Dickson, C Bancher, M Tabaton; citation_volume=55; citation_publication_date=1996; citation_pages=97-105; citation_doi=10.1097/00005072-199601000-00010; citation_id=CR73"/> <meta name="citation_reference" content="citation_journal_title=Nat Rev Neurol; citation_title=Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy; citation_author=CC Liu, CC Liu, T Kanekiyo, H Xu, G Bu; citation_volume=9; citation_publication_date=2013; citation_pages=106-118; citation_doi=10.1038/nrneurol.2012.263; citation_id=CR74"/> <meta name="citation_reference" content="citation_journal_title=EMBO J; citation_title=Cytoprotection by pre-emptive conditional phosphorylation of translation initiation factor 2; citation_author=PD Lu, C Jousse, SJ Marciniak, Y Zhang, I Novoa, D Scheuner, RJ Kaufman, D Ron, HP Harding; citation_volume=23; citation_publication_date=2004; citation_pages=169-179; citation_doi=10.1038/sj.emboj.7600030; citation_id=CR75"/> <meta name="citation_reference" content="citation_journal_title=J Neurol; citation_title=The prevalence and incidence of progressive supranuclear palsy and corticobasal syndrome: a systematic review and meta-analysis; citation_author=S Lyons, D Trepel, T Lynch, R Walsh, S O'Dowd; citation_volume=270; citation_publication_date=2023; citation_pages=4451-4465; citation_doi=10.1007/s00415-023-11791-2; citation_id=CR76"/> <meta name="citation_reference" content="citation_journal_title=Nature; citation_title=Single-cell transcriptomic analysis of Alzheimer's disease; citation_author=H Mathys, J Davila-Velderrain, Z Peng, F Gao, S Mohammadi, JZ Young, M Menon, L He, F Abdurrob, X Jiang; citation_volume=570; citation_publication_date=2019; citation_pages=332-337; citation_doi=10.1038/s41586-019-1195-2; citation_id=CR77"/> <meta name="citation_reference" content="citation_journal_title=Can J Neurol Sci; citation_title=Altered gene expression in Alzheimer's disease brain tissue; citation_author=PC May, SA Johnson, J Poirier, M Lampert-Etchells, CE Finch; citation_volume=16; citation_publication_date=1989; citation_pages=473-476; citation_doi=10.1017/s0317167100029796; citation_id=CR78"/> <meta name="citation_reference" content="citation_journal_title=Bioinformatics; citation_title=Testing significance relative to a fold-change threshold is a TREAT; citation_author=DJ McCarthy, GK Smyth; citation_volume=25; citation_publication_date=2009; citation_pages=765-771; citation_doi=10.1093/bioinformatics/btp053; citation_id=CR79"/> <meta name="citation_reference" content="citation_journal_title=Cell Syst; citation_title=DoubletFinder: doublet detection in single-cell RNA sequencing data using artificial nearest neighbors; citation_author=CS McGinnis, LM Murrow, ZJ Gartner; citation_volume=8; citation_issue=329–337; citation_publication_date=2019; citation_doi=10.1016/j.cels.2019.03.003; citation_id=CR80"/> <meta name="citation_reference" content="citation_journal_title=Sci Rep; citation_title=Brain cell type specific gene expression and co-expression network architectures; citation_author=AT McKenzie, M Wang, ME Hauberg, JF Fullard, A Kozlenkov, A Keenan, YL Hurd, S Dracheva, P Casaccia, P Roussos; citation_volume=8; citation_publication_date=2018; citation_pages=8868; citation_doi=10.1038/s41598-018-27293-5; citation_id=CR81"/> <meta name="citation_reference" content="citation_journal_title=Elife; citation_title=Neuropathological and transcriptomic characteristics of the aged brain; citation_author=JA Miller, A Guillozet-Bongaarts, LE Gibbons, N Postupna, A Renz, AE Beller, SM Sunkin, L Ng, SE Rose, KA Smith; citation_publication_date=2017; citation_doi=10.7554/eLife.31126; citation_id=CR82"/> <meta name="citation_reference" content="citation_journal_title=Nat Commun; citation_title=Cross species systems biology discovers glial DDR2, STOM, and KANK2 as therapeutic targets in progressive supranuclear palsy; citation_author=Y Min, X Wang, O Is, TA Patel, J Gao, JS Reddy, ZS Quicksall, T Nguyen, S Lin, FQ Tutor-New; citation_volume=14; citation_publication_date=2023; citation_pages=6801; citation_doi=10.1038/s41467-023-42626-3; citation_id=CR83"/> <meta name="citation_reference" content="citation_journal_title=J Pathol; citation_title=The unfolded protein response is associated with early tau pathology in the hippocampus of tauopathies; citation_author=DA Nijholt, ES Haastert, AJ Rozemuller, W Scheper, JJ Hoozemans; citation_volume=226; citation_publication_date=2012; citation_pages=693-702; citation_doi=10.1002/path.3969; citation_id=CR84"/> <meta name="citation_reference" content="citation_journal_title=Neuron; citation_title=Molecular signatures underlying neurofibrillary tangle susceptibility in Alzheimer's disease; citation_author=M Otero-Garcia, SU Mahajani, D Wakhloo, W Tang, YQ Xue, S Morabito, J Pan, J Oberhauser, AE Madira, T Shakouri; citation_volume=110; citation_issue=2929–2948; citation_publication_date=2022; citation_doi=10.1016/j.neuron.2022.06.021; citation_id=CR85"/> <meta name="citation_reference" content="citation_journal_title=EMBO Rep; citation_title=The integrated stress response; citation_author=K Pakos-Zebrucka, I Koryga, K Mnich, M Ljujic, A Samali, AM Gorman; citation_volume=17; citation_publication_date=2016; citation_pages=1374-1395; citation_doi=10.15252/embr.201642195; citation_id=CR86"/> <meta name="citation_reference" content="citation_journal_title=J Biol Chem; citation_title=Neurodegeneration risk factor, EIF2AK3 (PERK), influences tau protein aggregation; citation_author=G Park, K Xu, L Chea, K Kim, L Safarta, KH Song, J Wu, S Park, H Min, N Hiramatsu; citation_volume=299; citation_publication_date=2023; citation_doi=10.1016/j.jbc.2022.102821; citation_id=CR87"/> <meta name="citation_reference" content="citation_journal_title=Science; citation_title=Human CNS barrier-forming organoids with cerebrospinal fluid production; citation_author=L Pellegrini, C Bonfio, J Chadwick, F Begum, M Skehel, MA Lancaster; citation_publication_date=2020; citation_doi=10.1126/science.aaz5626; citation_id=CR88"/> <meta name="citation_reference" content="citation_journal_title=J Biol Chem; citation_title=Pathogenic tau does not drive activation of the unfolded protein response; citation_author=AP Pitera, AA Asuni, V O'Connor, K Deinhardt; citation_volume=294; citation_publication_date=2019; citation_pages=9679-9688; citation_doi=10.1074/jbc.RA119.008263; citation_id=CR89"/> <meta name="citation_reference" content="citation_journal_title=J Alzheimers Dis Rep; citation_title=Molecular investigation of the unfolded protein response in select human tauopathies; citation_author=AP Pitera, IJ Hartnell, L Scullard, KL Williamson, D Boche, V O'Connor, K Deinhardt; citation_volume=5; citation_publication_date=2021; citation_pages=855-869; citation_doi=10.3233/ADR-210050; citation_id=CR90"/> <meta name="citation_reference" content="citation_journal_title=PLoS ONE; citation_title=IFI6 inhibits apoptosis via mitochondrial-dependent pathway in dengue virus 2 infected vascular endothelial cells; citation_author=Y Qi, Y Li, Y Zhang, L Zhang, Z Wang, X Zhang, L Gui, J Huang; citation_volume=10; citation_publication_date=2015; citation_doi=10.1371/journal.pone.0132743; citation_id=CR91"/> <meta name="citation_reference" content="citation_journal_title=J Alzheimers Dis; citation_title=Activation of protein phosphatase 2B and hyperphosphorylation of Tau in Alzheimer's disease; citation_author=W Qian, X Yin, W Hu, J Shi, J Gu, I Grundke-Iqbal, K Iqbal, CX Gong, F Liu; citation_volume=23; citation_publication_date=2011; citation_pages=617-627; citation_doi=10.3233/JAD-2010-100987; citation_id=CR92"/> <meta name="citation_reference" content="citation_journal_title=J Struct Biol; citation_title=Study of the localization of iron, ferritin, and hemosiderin in Alzheimer's disease hippocampus by analytical microscopy at the subcellular level; citation_author=C Quintana, S Bellefqih, JY Laval, JL Guerquin-Kern, TD Wu, J Avila, I Ferrer, R Arranz, C Patino; citation_volume=153; citation_publication_date=2006; citation_pages=42-54; citation_doi=10.1016/j.jsb.2005.11.001; citation_id=CR93"/> <meta name="citation_reference" content="citation_journal_title=J Neural Transm (Vienna); citation_title=PP2B isolated from human brain preferentially dephosphorylates Ser-262 and Ser-396 of the Alzheimer disease abnormally hyperphosphorylated tau; citation_author=A Rahman, I Grundke-Iqbal, K Iqbal; citation_volume=113; citation_publication_date=2006; citation_pages=219-230; citation_doi=10.1007/s00702-005-0313-5; citation_id=CR94"/> <meta name="citation_reference" content="citation_journal_title=Mol Neurodegener; citation_title=ApoE in Alzheimer's disease: pathophysiology and therapeutic strategies; citation_author=AC Raulin, SV Doss, ZA Trottier, TC Ikezu, G Bu, CC Liu; citation_volume=17; citation_publication_date=2022; citation_pages=72; citation_doi=10.1186/s13024-022-00574-4; citation_id=CR95"/> <meta name="citation_reference" content="citation_journal_title=Proc Natl Acad Sci U S A; citation_title=Pw1/Peg3 is a potential cell death mediator and cooperates with Siah1a in p53-mediated apoptosis; citation_author=F Relaix, X Wei, W Li, J Pan, Y Lin, DD Bowtell, DA Sassoon, X Wu; citation_volume=97; citation_publication_date=2000; citation_pages=2105-2110; citation_doi=10.1073/pnas.040378897; citation_id=CR96"/> <meta name="citation_reference" content="citation_journal_title=Front Aging Neurosci; citation_title=The cross-links of endoplasmic reticulum stress, autophagy, and neurodegeneration in Parkinson’s disease; citation_author=H Ren, W Zhai, X Lu, G Wang; citation_volume=13; citation_publication_date=2021; citation_doi=10.3389/fnagi.2021.691881; citation_id=CR97"/> <meta name="citation_reference" content="citation_journal_title=Acta Neuropathol Commun; citation_title=MAPT haplotype-associated transcriptomic changes in progressive supranuclear palsy; citation_author=HW Ressler, J Humphrey, RA Vialle, B Babrowicz, S Kandoi, T Raj, DW Dickson, N Ertekin-Taner, JF Crary, K Farrell; citation_volume=12; citation_publication_date=2024; citation_pages=135; citation_doi=10.1186/s40478-024-01839-3; citation_id=CR98"/> <meta name="citation_reference" content="citation_journal_title=Nat Commun; citation_title=Single cell transcriptomic profiling of a neuron-astrocyte assembloid tauopathy model; citation_author=HD Rickner, L Jiang, R Hong, NK O'Neill, CA Mojica, BJ Snyder, L Zhang, D Shaw, M Medalla, B Wolozin; citation_volume=13; citation_publication_date=2022; citation_pages=6275; citation_doi=10.1038/s41467-022-34005-1; citation_id=CR99"/> <meta name="citation_reference" content="citation_journal_title=Dement Neuropsychol; citation_title=Argyrophilic grain disease: an underestimated tauopathy; citation_author=RD Rodriguez, LT Grinberg; citation_volume=9; citation_publication_date=2015; citation_pages=2-8; citation_doi=10.1590/S1980-57642015DN91000002; citation_id=CR100"/> <meta name="citation_reference" content="citation_journal_title=Acta Neuropathol; citation_title=Rainwater charitable foundation criteria for the neuropathologic diagnosis of progressive supranuclear palsy; citation_author=SF Roemer, LT Grinberg, JF Crary, WW Seeley, AC McKee, GG Kovacs, TG Beach, C Duyckaerts, IA Ferrer, E Gelpi; citation_volume=144; citation_publication_date=2022; citation_pages=603-614; citation_doi=10.1007/s00401-022-02479-4; citation_id=CR101"/> <meta name="citation_reference" content="citation_journal_title=Brain; citation_title=Clinical genetics of familial progressive supranuclear palsy; citation_author=A Rojo, RS Pernaute, A Fontan, PG Ruiz, J Honnorat, T Lynch, S Chin, I Gonzalo, A Rabano, A Martinez; citation_volume=122; citation_issue=Pt 7; citation_publication_date=1999; citation_pages=1233-1245; citation_doi=10.1093/brain/122.7.1233; citation_id=CR102"/> <meta name="citation_reference" content="citation_journal_title=PLoS ONE; citation_title=Oligodendrocyte precursor cells synthesize neuromodulatory factors; citation_author=D Sakry, H Yigit, L Dimou, J Trotter; citation_volume=10; citation_publication_date=2015; citation_doi=10.1371/journal.pone.0127222; citation_id=CR103"/> <meta name="citation_reference" content="citation_journal_title=Mol Neurodegener; citation_title=Replication of progressive supranuclear palsy genome-wide association study identifies SLCO1A2 and DUSP10 as new susceptibility loci; citation_author=MY Sanchez-Contreras, N Kouri, CN Cook, DJ Serie, MG Heckman, NA Finch, RJ Caselli, RJ Uitti, ZK Wszolek, N Graff-Radford; citation_volume=13; citation_publication_date=2018; citation_pages=37; citation_doi=10.1186/s13024-018-0267-3; citation_id=CR104"/> <meta name="citation_reference" content="citation_journal_title=Acta Neuropathol; citation_title=The unfolded protein response in neurodegenerative diseases: a neuropathological perspective; citation_author=W Scheper, JJ Hoozemans; citation_volume=130; citation_publication_date=2015; citation_pages=315-331; citation_doi=10.1007/s00401-015-1462-8; citation_id=CR105"/> <meta name="citation_reference" content="citation_journal_title=J Vasc Res; citation_title=Expression, regulation and function of human metallothioneins in endothelial cells; citation_author=IA Schulkens, KC Castricum, EM Weijers, P Koolwijk, AW Griffioen, VL Thijssen; citation_volume=51; citation_publication_date=2014; citation_pages=231-238; citation_doi=10.1159/000365550; citation_id=CR106"/> <meta name="citation_reference" content="citation_journal_title=Exp Mol Med; citation_title=Transcriptome analyses of chronic traumatic encephalopathy show alterations in protein phosphatase expression associated with tauopathy; citation_author=JS Seo, S Lee, JY Shin, YJ Hwang, H Cho, SK Yoo, Y Kim, S Lim, YK Kim, EM Hwang; citation_volume=49; citation_publication_date=2017; citation_doi=10.1038/emm.2017.56; citation_id=CR107"/> <meta name="citation_reference" content="Shah H, CW Y, Castellanos R, Pandya C, Giles Z (2015) RAPiD—an agile and dependable RNA-Seq framework. The 65th annual meeting of the American society of human genetics, City"/> <meta name="citation_reference" content="citation_journal_title=Stem Cell Reports; citation_title=Human iPSC-derived neuronal model of Tau-A152T frontotemporal dementia reveals Tau-mediated mechanisms of neuronal vulnerability; citation_author=MC Silva, C Cheng, W Mair, S Almeida, H Fong, MHU Biswas, Z Zhang, Y Huang, S Temple, G Coppola; citation_volume=7; citation_publication_date=2016; citation_pages=325-340; citation_doi=10.1016/j.stemcr.2016.08.001; citation_id=CR109"/> <meta name="citation_reference" content="citation_journal_title=Brain; citation_title=Single-cell sequencing of human midbrain reveals glial activation and a Parkinson-specific neuronal state; citation_author=S Smajic, CA Prada-Medina, Z Landoulsi, J Ghelfi, S Delcambre, C Dietrich, J Jarazo, J Henck, S Balachandran, S Pachchek; citation_volume=145; citation_publication_date=2022; citation_pages=964-978; citation_doi=10.1093/brain/awab446; citation_id=CR110"/> <meta name="citation_reference" content="citation_journal_title=Neuron; citation_title=Astrocyte unfolded protein response induces a specific reactivity state that causes non-cell-autonomous neuronal degeneration; citation_author=HL Smith, OJ Freeman, AJ Butcher, S Holmqvist, I Humoud, T Schatzl, DT Hughes, NC Verity, DP Swinden, J Hayes; citation_volume=105; citation_issue=855–866; citation_publication_date=2020; citation_doi=10.1016/j.neuron.2019.12.014; citation_id=CR111"/> <meta name="citation_reference" content="citation_journal_title=J Biol Chem; citation_title=Phosphorylation of eukaryotic translation initiation factor 2 mediates apoptosis in response to activation of the double-stranded RNA-dependent protein kinase; citation_author=SP Srivastava, KU Kumar, RJ Kaufman; citation_volume=273; citation_publication_date=1998; citation_pages=2416-2423; citation_doi=10.1074/jbc.273.4.2416; citation_id=CR112"/> <meta name="citation_reference" content="citation_journal_title=EMBO J; citation_title=Phosphorylation of microtubule-associated protein tau: identification of the site for Ca2(+)-calmodulin dependent kinase and relationship with tau phosphorylation in Alzheimer tangles; citation_author=B Steiner, EM Mandelkow, J Biernat, N Gustke, HE Meyer, B Schmidt, G Mieskes, HD Soling, D Drechsel, MW Kirschner; citation_volume=9; citation_publication_date=1990; citation_pages=3539-3544; citation_doi=10.1002/j.1460-2075.1990.tb07563.x; citation_id=CR113"/> <meta name="citation_reference" content="citation_journal_title=Cell; citation_title=Comprehensive integration of single-cell data; citation_author=T Stuart, A Butler, P Hoffman, C Hafemeister, E Papalexi, WM Mauck, Y Hao, M Stoeckius, P Smibert, R Satija; citation_volume=177; citation_issue=1888–1902; citation_publication_date=2019; citation_doi=10.1016/j.cell.2019.05.031; citation_id=CR114"/> <meta name="citation_reference" content="citation_journal_title=Acta Neuropathol Commun; citation_title=The unfolded protein response is activated in disease-affected brain regions in progressive supranuclear palsy and Alzheimer's disease; citation_author=LD Stutzbach, SX Xie, AC Naj, R Albin, S Gilman, VM Lee, JQ Trojanowski, B Devlin, GD Schellenberg; citation_volume=1; citation_publication_date=2013; citation_pages=31; citation_doi=10.1186/2051-5960-1-31; citation_id=CR115"/> <meta name="citation_reference" content="citation_journal_title=Proc Natl Acad Sci U S A; citation_title=Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles; citation_author=A Subramanian, P Tamayo, VK Mootha, S Mukherjee, BL Ebert, MA Gillette, A Paulovich, SL Pomeroy, TR Golub, ES Lander; citation_volume=102; citation_publication_date=2005; citation_pages=15545-15550; citation_doi=10.1073/pnas.0506580102; citation_id=CR116"/> <meta name="citation_reference" content="citation_journal_title=Nat Rev Neurol; citation_title=Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders; citation_author=MD Sweeney, AP Sagare, BV Zlokovic; citation_volume=14; citation_publication_date=2018; citation_pages=133-150; citation_doi=10.1038/nrneurol.2017.188; citation_id=CR117"/> <meta name="citation_reference" content="citation_journal_title=J Can Acad Child Adolesc Psychiatry; citation_title=Explaining odds ratios; citation_author=M Szumilas; citation_volume=19; citation_publication_date=2010; citation_pages=227-229; citation_id=CR118"/> <meta name="citation_reference" content="citation_journal_title=Sci Rep; citation_title=Integrated stress response of vertebrates is regulated by four eIF2alpha kinases; citation_author=S Taniuchi, M Miyake, K Tsugawa, M Oyadomari, S Oyadomari; citation_volume=6; citation_publication_date=2016; citation_pages=32886; citation_doi=10.1038/srep32886; citation_id=CR119"/> <meta name="citation_reference" content="citation_journal_title=Hum Mol Genet; citation_title=MAPT expression and splicing is differentially regulated by brain region: relation to genotype and implication for tauopathies; citation_author=D Trabzuni, S Wray, J Vandrovcova, A Ramasamy, R Walker, C Smith, C Luk, JR Gibbs, A Dillman, DG Hernandez; citation_volume=21; citation_publication_date=2012; citation_pages=4094-4103; citation_doi=10.1093/hmg/dds238; citation_id=CR120"/> <meta name="citation_reference" content="citation_journal_title=J Neuropathol Exp Neurol; citation_title=Endoplasmic reticulum stress features are prominent in Alzheimer disease but not in prion diseases in vivo; citation_author=U Unterberger, R Hoftberger, E Gelpi, H Flicker, H Budka, T Voigtlander; citation_volume=65; citation_publication_date=2006; citation_pages=348-357; citation_doi=10.1097/01.jnen.0000218445.30535.6f; citation_id=CR121"/> <meta name="citation_reference" content="citation_journal_title=Neuroscience; citation_title=PEP-19 immunohistochemistry defines the basal ganglia and associated structures in the adult human brain, and is dramatically reduced in Huntington's disease; citation_author=AK Utal, AL Stopka, M Roy, PD Coleman; citation_volume=86; citation_publication_date=1998; citation_pages=1055-1063; citation_doi=10.1016/s0306-4522(98)00130-4; citation_id=CR122"/> <meta name="citation_reference" content="citation_journal_title=BMC Biol; citation_title=Combined protein and transcript single-cell RNA sequencing in human peripheral blood mononuclear cells; citation_author=J Vallejo, R Saigusa, R Gulati, SS Armstrong Suthahar, V Suryawanshi, A Alimadadi, CP Durant, Y Ghosheh, P Roy, E Ehinger; citation_volume=20; citation_publication_date=2022; citation_pages=193; citation_doi=10.1186/s12915-022-01382-4; citation_id=CR123"/> <meta name="citation_reference" content="citation_journal_title=Mol Cell; citation_title=JunD protects cells from p53-dependent senescence and apoptosis; citation_author=JB Weitzman, L Fiette, K Matsuo, M Yaniv; citation_volume=6; citation_publication_date=2000; citation_pages=1109-1119; citation_doi=10.1016/s1097-2765(00)00109-x; citation_id=CR124"/> <meta name="citation_reference" content="citation_journal_title=Brain; citation_title=Pathological tau burden and distribution distinguishes progressive supranuclear palsy-parkinsonism from Richardson’s syndrome; citation_author=DR Williams, JL Holton, C Strand, A Pittman, R Silva, AJ Lees, T Revesz; citation_volume=130; citation_publication_date=2007; citation_pages=1566-1576; citation_doi=10.1093/brain/awm104; citation_id=CR125"/> <meta name="citation_reference" content="citation_journal_title=Cell; citation_title=Hallmarks of neurodegenerative diseases; citation_author=DM Wilson, MR Cookson, L Bosch, H Zetterberg, DM Holtzman, I Dewachter; citation_volume=186; citation_publication_date=2023; citation_pages=693-714; citation_doi=10.1016/j.cell.2022.12.032; citation_id=CR126"/> <meta name="citation_reference" content="citation_journal_title=Acta Neuropathol Commun; citation_title=Clusterin ameliorates tau pathology in vivo by inhibiting fibril formation; citation_author=AM Wojtas, Y Carlomagno, JP Sens, SS Kang, TD Jensen, A Kurti, KE Baker, TJ Berry, VR Phillips, MC Castanedes; citation_volume=8; citation_publication_date=2020; citation_pages=210; citation_doi=10.1186/s40478-020-01079-1; citation_id=CR127"/> <meta name="citation_reference" content="citation_journal_title=J Neuropathol Exp Neurol; citation_title=alpha-calcium-calmodulin-dependent kinase II is associated with paired helical filaments of Alzheimer’s disease; citation_author=J Xiao, G Perry, J Troncoso, MJ Monteiro; citation_volume=55; citation_publication_date=1996; citation_pages=954-963; citation_doi=10.1097/00005072-199609000-00002; citation_id=CR128"/> <meta name="citation_reference" content="citation_journal_title=Front Mol Neurosci; citation_title=The function of VAMP2 in mediating membrane fusion: an overview; citation_author=C Yan, J Jiang, Y Yang, X Geng, W Dong; citation_volume=15; citation_publication_date=2022; citation_doi=10.3389/fnmol.2022.948160; citation_id=CR129"/> <meta name="citation_reference" content="citation_journal_title=Sci Rep; citation_title=CELF2 regulates the species-specific alternative splicing of TREM2; citation_author=M Yanaizu, C Washizu, N Nukina, JI Satoh, Y Kino; citation_volume=10; citation_publication_date=2020; citation_pages=17995; citation_doi=10.1038/s41598-020-75057-x; citation_id=CR130"/> <meta name="citation_reference" content="citation_journal_title=Neurosci Lett; citation_title=Phosphorylation of tau protein to sites found in Alzheimer’s disease brain is catalyzed by Ca2+/calmodulin-dependent protein kinase II as demonstrated tandem mass spectrometry; citation_author=Y Yoshimura, T Ichinose, T Yamauchi; citation_volume=353; citation_publication_date=2003; citation_pages=185-188; citation_doi=10.1016/j.neulet.2003.09.037; citation_id=CR131"/> <meta name="citation_reference" content="citation_journal_title=Front Neurosci; citation_title=Neurofilament proteins as biomarkers to monitor neurological diseases and the efficacy of therapies; citation_author=A Yuan, RA Nixon; citation_volume=15; citation_publication_date=2021; citation_doi=10.3389/fnins.2021.689938; citation_id=CR132"/> <meta name="citation_reference" content="citation_journal_title=Front Aging Neurosci; citation_title=Humanin, a mitochondrial-derived peptide released by astrocytes, prevents synapse loss in hippocampal neurons; citation_author=SC Zarate, ME Traetta, MG Codagnone, A Seilicovich, AG Reines; citation_volume=11; citation_publication_date=2019; citation_pages=123; citation_doi=10.3389/fnagi.2019.00123; citation_id=CR133"/> <meta name="citation_author" content="Whitney, Kristen"/> <meta name="citation_author_institution" content="Department of Pathology, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, USA"/> <meta name="citation_author_institution" content="Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, USA"/> <meta name="citation_author_institution" content="Ronald M. 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Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, USA"/> <meta name="citation_author_institution" content="Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, USA"/> <meta name="citation_author" content="Crary, John F."/> <meta name="citation_author_email" content="john.crary@mountsinai.org"/> <meta name="citation_author_institution" content="Department of Pathology, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, USA"/> <meta name="citation_author_institution" content="Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, USA"/> <meta name="citation_author_institution" content="Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, USA"/> <meta name="citation_author_institution" content="Neuropathology Brain Bank & Research Core, Icahn School of Medicine at Mount Sinai, New York, USA"/> <meta name="citation_author_institution" content="Department of Artificial Intelligence & Human Health, Icahn School of Medicine at Mount Sinai, New York, USA"/> <meta name="citation_author_institution" content="Department of Neurology, James J. Peters Veterans Affairs Medical Center, Bronx, USA"/> <meta name="format-detection" content="telephone=no"/> <meta name="citation_cover_date" content="2024/12/01"/> <meta property="og:url" content="https://link.springer.com/article/10.1007/s00401-024-02823-w"/> <meta property="og:type" content="article"/> <meta property="og:site_name" content="SpringerLink"/> <meta property="og:title" content="Single-cell transcriptomic and neuropathologic analysis reveals dysregulation of the integrated stress response in progressive supranuclear palsy - Acta Neuropathologica"/> <meta property="og:description" content="Progressive supranuclear palsy (PSP) is a sporadic neurodegenerative tauopathy variably affecting brainstem and cortical structures, and characterized by tau inclusions in neurons and glia. The precise mechanism whereby these protein aggregates lead to cell death remains unclear. To investigate the contribution of these different cellular abnormalities to PSP pathogenesis, we performed single-nucleus RNA sequencing (snRNA-seq) and analyzed 50,708 high quality nuclei targeting the diencephalon, including the subthalamic nucleus and adjacent structures, from human post-mortem PSP brains with varying degrees of pathology compared to controls. Cell-type-specific differential expression and pathway analysis identified both common and discrete changes in numerous pathways previously implicated in PSP and other neurodegenerative disorders. This included EIF2 signaling, an adaptive pathway activated in response to diverse stressors, which was activated in multiple vulnerable cell types and validated in independent snRNA-seq and bulk RNA-seq datasets. Using immunohistochemistry, we found that activated eIF2α was positively correlated with tau pathology burden in vulnerable brain regions. Multiplex immunofluorescence localized activated eIF2α positivity to hyperphosphorylated tau (p-tau) positive neurons and ALDH1L1-positive astrocytes, supporting the increased transcriptomic EIF2 activation observed in these vulnerable cell types. In conclusion, these data provide insights into cell-type-specific pathological changes in PSP and support the hypothesis that failure of adaptive stress pathways play a mechanistic role in the pathogenesis and progression of PSP."/> <meta property="og:image" content="https://static-content.springer.com/image/art%3A10.1007%2Fs00401-024-02823-w/MediaObjects/401_2024_2823_Fig1_HTML.png"/> <meta name="format-detection" content="telephone=no"> <link rel="apple-touch-icon" sizes="180x180" href=/oscar-static/img/favicons/darwin/apple-touch-icon-92e819bf8a.png> <link rel="icon" type="image/png" sizes="192x192" href=/oscar-static/img/favicons/darwin/android-chrome-192x192-6f081ca7e5.png> <link rel="icon" type="image/png" sizes="32x32" href=/oscar-static/img/favicons/darwin/favicon-32x32-1435da3e82.png> <link rel="icon" type="image/png" sizes="16x16" href=/oscar-static/img/favicons/darwin/favicon-16x16-ed57f42bd2.png> <link rel="shortcut icon" data-test="shortcut-icon" 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The precise mechanism whereby these protein aggregates lead to cell death remains unclear. To investigate the contribution of these different cellular abnormalities to PSP pathogenesis, we performed single-nucleus RNA sequencing (snRNA-seq) and analyzed 50,708 high quality nuclei targeting the diencephalon, including the subthalamic nucleus and adjacent structures, from human post-mortem PSP brains with varying degrees of pathology compared to controls. Cell-type-specific differential expression and pathway analysis identified both common and discrete changes in numerous pathways previously implicated in PSP and other neurodegenerative disorders. This included EIF2 signaling, an adaptive pathway activated in response to diverse stressors, which was activated in multiple vulnerable cell types and validated in independent snRNA-seq and bulk RNA-seq datasets. Using immunohistochemistry, we found that activated eIF2α was positively correlated with tau pathology burden in vulnerable brain regions. Multiplex immunofluorescence localized activated eIF2α positivity to hyperphosphorylated tau (p-tau) positive neurons and ALDH1L1-positive astrocytes, supporting the increased transcriptomic EIF2 activation observed in these vulnerable cell types. 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</div> </div> </div> <div class="c-article-header"> <header> <ul class="c-article-author-list c-article-author-list--short" data-test="authors-list" data-component-authors-activator="authors-list"><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Kristen-Whitney-Aff1-Aff2-Aff3-Aff4-Aff5" data-author-popup="auth-Kristen-Whitney-Aff1-Aff2-Aff3-Aff4-Aff5" data-author-search="Whitney, Kristen">Kristen Whitney</a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff2">2</a>,<a href="#Aff3">3</a>,<a href="#Aff4">4</a>,<a href="#Aff5">5</a></sup>, </li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Won_Min-Song-Aff6-Aff7-Aff8" data-author-popup="auth-Won_Min-Song-Aff6-Aff7-Aff8" data-author-search="Song, Won-Min" data-corresp-id="c1">Won-Min Song<svg width="16" height="16" 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data-author-popup="auth-Diana_K_-Dangoor-Aff1-Aff2-Aff3-Aff4-Aff5" data-author-search="Dangoor, Diana K.">Diana K. Dangoor</a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff2">2</a>,<a href="#Aff3">3</a>,<a href="#Aff4">4</a>,<a href="#Aff5">5</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Kurt-Farrell-Aff1-Aff2-Aff3-Aff4-Aff5" data-author-popup="auth-Kurt-Farrell-Aff1-Aff2-Aff3-Aff4-Aff5" data-author-search="Farrell, Kurt">Kurt Farrell</a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff2">2</a>,<a href="#Aff3">3</a>,<a href="#Aff4">4</a>,<a href="#Aff5">5</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Margaret_M_-Krassner-Aff1-Aff2-Aff3-Aff4-Aff5" data-author-popup="auth-Margaret_M_-Krassner-Aff1-Aff2-Aff3-Aff4-Aff5" data-author-search="Krassner, Margaret M.">Margaret M. Krassner</a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff2">2</a>,<a href="#Aff3">3</a>,<a href="#Aff4">4</a>,<a href="#Aff5">5</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Hadley_W_-Ressler-Aff1-Aff2-Aff3-Aff4-Aff5" data-author-popup="auth-Hadley_W_-Ressler-Aff1-Aff2-Aff3-Aff4-Aff5" data-author-search="Ressler, Hadley W.">Hadley W. Ressler</a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff2">2</a>,<a href="#Aff3">3</a>,<a href="#Aff4">4</a>,<a href="#Aff5">5</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Thomas_D_-Christie-Aff1-Aff2-Aff3-Aff4-Aff5" data-author-popup="auth-Thomas_D_-Christie-Aff1-Aff2-Aff3-Aff4-Aff5" data-author-search="Christie, Thomas D.">Thomas D. Christie</a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff2">2</a>,<a href="#Aff3">3</a>,<a href="#Aff4">4</a>,<a href="#Aff5">5</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Shrishtee-Kandoi-Aff1-Aff2-Aff3-Aff4-Aff5" data-author-popup="auth-Shrishtee-Kandoi-Aff1-Aff2-Aff3-Aff4-Aff5" data-author-search="Kandoi, Shrishtee">Shrishtee Kandoi</a><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff2">2</a>,<a href="#Aff3">3</a>,<a href="#Aff4">4</a>,<a href="#Aff5">5</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Ruth_H_-Walker-Aff9-Aff12" data-author-popup="auth-Ruth_H_-Walker-Aff9-Aff12" data-author-search="Walker, Ruth H.">Ruth H. Walker</a><sup class="u-js-hide"><a href="#Aff9">9</a>,<a href="#Aff12">12</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Melissa_J_-Nirenberg-Aff9-Aff12" data-author-popup="auth-Melissa_J_-Nirenberg-Aff9-Aff12" data-author-search="Nirenberg, Melissa J.">Melissa J. Nirenberg</a><sup class="u-js-hide"><a href="#Aff9">9</a>,<a href="#Aff12">12</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Steven_J_-Frucht-Aff11" data-author-popup="auth-Steven_J_-Frucht-Aff11" data-author-search="Frucht, Steven J.">Steven J. Frucht</a><sup class="u-js-hide"><a href="#Aff11">11</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Giulietta_M_-Riboldi-Aff11" data-author-popup="auth-Giulietta_M_-Riboldi-Aff11" data-author-search="Riboldi, Giulietta M.">Giulietta M. Riboldi</a><sup class="u-js-hide"><a href="#Aff11">11</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Bin-Zhang-Aff6-Aff7-Aff8-Aff10" data-author-popup="auth-Bin-Zhang-Aff6-Aff7-Aff8-Aff10" data-author-search="Zhang, Bin">Bin Zhang</a><sup class="u-js-hide"><a href="#Aff6">6</a>,<a href="#Aff7">7</a>,<a href="#Aff8">8</a>,<a href="#Aff10">10</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Ana_C_-Pereira-Aff2-Aff3-Aff9" data-author-popup="auth-Ana_C_-Pereira-Aff2-Aff3-Aff9" data-author-search="Pereira, Ana C." data-corresp-id="c2">Ana C. Pereira<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-mail-medium"></use></svg></a><sup class="u-js-hide"><a href="#Aff2">2</a>,<a href="#Aff3">3</a>,<a href="#Aff9">9</a></sup> & </li><li class="c-article-author-list__show-more" aria-label="Show all 16 authors for this article" title="Show all 16 authors for this article">…</li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-John_F_-Crary-Aff1-Aff2-Aff3-Aff4-Aff5-Aff12" data-author-popup="auth-John_F_-Crary-Aff1-Aff2-Aff3-Aff4-Aff5-Aff12" data-author-search="Crary, John F." data-corresp-id="c3">John F. Crary<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-mail-medium"></use></svg></a><span class="u-js-hide"> <a class="js-orcid" href="http://orcid.org/0000-0002-0556-293X"><span class="u-visually-hidden">ORCID: </span>orcid.org/0000-0002-0556-293X</a></span><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff2">2</a>,<a href="#Aff3">3</a>,<a href="#Aff4">4</a>,<a href="#Aff5">5</a>,<a href="#Aff12">12</a></sup> </li></ul><button aria-expanded="false" class="c-article-author-list__button"><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-down-medium"></use></svg><span>Show authors</span></button> <div data-test="article-metrics"> <ul class="app-article-metrics-bar u-list-reset"> <li class="app-article-metrics-bar__item"> <p class="app-article-metrics-bar__count"><svg class="u-icon app-article-metrics-bar__icon" width="24" height="24" aria-hidden="true" focusable="false"> <use xlink:href="#icon-eds-i-accesses-medium"></use> </svg>1117 <span class="app-article-metrics-bar__label">Accesses</span></p> </li> <li class="app-article-metrics-bar__item"> <p class="app-article-metrics-bar__count"><svg class="u-icon app-article-metrics-bar__icon" width="24" height="24" aria-hidden="true" focusable="false"> <use xlink:href="#icon-eds-i-altmetric-medium"></use> </svg>12 <span class="app-article-metrics-bar__label">Altmetric</span></p> </li> <li class="app-article-metrics-bar__item"> <p class="app-article-metrics-bar__count"><svg class="u-icon app-article-metrics-bar__icon app-article-metrics-bar__icon--mentions" width="24" height="24" aria-hidden="true" focusable="false"> <use xlink:href="#icon-eds-i-mentions-medium"></use> </svg>1 <span class="app-article-metrics-bar__label">Mention</span></p> </li> <li class="app-article-metrics-bar__item app-article-metrics-bar__item--metrics"> <p class="app-article-metrics-bar__details"><a href="/article/10.1007/s00401-024-02823-w/metrics" data-track="click" data-track-action="view metrics" data-track-label="link" rel="nofollow">Explore all metrics <svg class="u-icon app-article-metrics-bar__arrow-icon" width="24" height="24" aria-hidden="true" focusable="false"> <use xlink:href="#icon-eds-i-arrow-right-medium"></use> </svg></a></p> </li> </ul> </div> <div class="u-mt-32"> </div> </header> </div> <div data-article-body="true" data-track-component="article body" class="c-article-body"> <section aria-labelledby="Abs1" data-title="Abstract" lang="en"><div class="c-article-section" id="Abs1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Abs1">Abstract</h2><div class="c-article-section__content" id="Abs1-content"><p>Progressive supranuclear palsy (PSP) is a sporadic neurodegenerative tauopathy variably affecting brainstem and cortical structures, and characterized by tau inclusions in neurons and glia. The precise mechanism whereby these protein aggregates lead to cell death remains unclear. To investigate the contribution of these different cellular abnormalities to PSP pathogenesis, we performed single-nucleus RNA sequencing (snRNA-seq) and analyzed 50,708 high quality nuclei targeting the diencephalon, including the subthalamic nucleus and adjacent structures, from human post-mortem PSP brains with varying degrees of pathology compared to controls. Cell-type-specific differential expression and pathway analysis identified both common and discrete changes in numerous pathways previously implicated in PSP and other neurodegenerative disorders. This included EIF2 signaling, an adaptive pathway activated in response to diverse stressors, which was activated in multiple vulnerable cell types and validated in independent snRNA-seq and bulk RNA-seq datasets. Using immunohistochemistry, we found that activated eIF2α was positively correlated with tau pathology burden in vulnerable brain regions. Multiplex immunofluorescence localized activated eIF2α positivity to hyperphosphorylated tau (p-tau) positive neurons and ALDH1L1-positive astrocytes, supporting the increased transcriptomic EIF2 activation observed in these vulnerable cell types. In conclusion, these data provide insights into cell-type-specific pathological changes in PSP and support the hypothesis that failure of adaptive stress pathways play a mechanistic role in the pathogenesis and progression of PSP.</p></div></div></section> <div data-test="cobranding-download"> </div> <section aria-labelledby="inline-recommendations" data-title="Inline Recommendations" class="c-article-recommendations" data-track-component="inline-recommendations"> <h3 class="c-article-recommendations-title" id="inline-recommendations">Similar content being viewed by others</h3> <div class="c-article-recommendations-list"> <div class="c-article-recommendations-list__item"> <article class="c-article-recommendations-card" itemscope itemtype="http://schema.org/ScholarlyArticle"> <div class="c-article-recommendations-card__img"><img src="https://media.springernature.com/w215h120/springer-static/image/art%3A10.1007%2Fs00401-018-1870-7/MediaObjects/401_2018_1870_Fig1_HTML.png" loading="lazy" alt=""></div> <div class="c-article-recommendations-card__main"> <h3 class="c-article-recommendations-card__heading" itemprop="name headline"> <a class="c-article-recommendations-card__link" itemprop="url" href="https://link.springer.com/10.1007/s00401-018-1870-7?fromPaywallRec=false" data-track="select_recommendations_1" data-track-context="inline recommendations" data-track-action="click recommendations inline - 1" data-track-label="10.1007/s00401-018-1870-7">Transcriptome–pathology correlation identifies interplay between TDP-43 and the expression of its kinase CK1E in sporadic ALS </a> </h3> <div class="c-article-meta-recommendations" data-test="recommendation-info"> <span class="c-article-meta-recommendations__item-type">Article</span> <span class="c-article-meta-recommendations__date">07 June 2018</span> </div> </div> </article> </div> <div class="c-article-recommendations-list__item"> <article class="c-article-recommendations-card" itemscope itemtype="http://schema.org/ScholarlyArticle"> <div class="c-article-recommendations-card__img"><img src="https://media.springernature.com/w215h120/springer-static/image/art%3A10.1007%2Fs00401-022-02483-8/MediaObjects/401_2022_2483_Fig1_HTML.png" loading="lazy" alt=""></div> <div class="c-article-recommendations-card__main"> <h3 class="c-article-recommendations-card__heading" itemprop="name headline"> <a class="c-article-recommendations-card__link" itemprop="url" href="https://link.springer.com/10.1007/s00401-022-02483-8?fromPaywallRec=false" data-track="select_recommendations_2" data-track-context="inline recommendations" data-track-action="click recommendations inline - 2" data-track-label="10.1007/s00401-022-02483-8">Single-nucleus chromatin accessibility profiling highlights distinct astrocyte signatures in progressive supranuclear palsy and corticobasal degeneration </a> </h3> <div class="c-article-meta-recommendations" data-test="recommendation-info"> <span class="c-article-meta-recommendations__item-type">Article</span> <span class="c-article-meta-recommendations__access-type">Open access</span> <span class="c-article-meta-recommendations__date">17 August 2022</span> </div> </div> </article> </div> <div class="c-article-recommendations-list__item"> <article class="c-article-recommendations-card" itemscope itemtype="http://schema.org/ScholarlyArticle"> <div class="c-article-recommendations-card__img"><img src="https://media.springernature.com/w215h120/springer-static/image/art%3A10.1038%2Fs42003-023-05041-4/MediaObjects/42003_2023_5041_Fig1_HTML.png" loading="lazy" alt=""></div> <div class="c-article-recommendations-card__main"> <h3 class="c-article-recommendations-card__heading" itemprop="name headline"> <a class="c-article-recommendations-card__link" itemprop="url" href="https://link.springer.com/10.1038/s42003-023-05041-4?fromPaywallRec=false" data-track="select_recommendations_3" data-track-context="inline recommendations" data-track-action="click recommendations inline - 3" data-track-label="10.1038/s42003-023-05041-4">A human proteogenomic-cellular framework identifies KIF5A as a modulator of astrocyte process integrity with relevance to ALS </a> </h3> <div class="c-article-meta-recommendations" data-test="recommendation-info"> <span class="c-article-meta-recommendations__item-type">Article</span> <span class="c-article-meta-recommendations__access-type">Open access</span> <span class="c-article-meta-recommendations__date">29 June 2023</span> </div> </div> </article> </div> </div> </section> <script> window.dataLayer = window.dataLayer || []; window.dataLayer.push({ recommendations: { recommender: 'semantic', model: 'specter', policy_id: 'NA', timestamp: 1735090660, embedded_user: 'null' } }); </script> <div class="app-card-service" data-test="article-checklist-banner"> <div> <a class="app-card-service__link" data-track="click_presubmission_checklist" data-track-context="article page top of reading companion" data-track-category="pre-submission-checklist" data-track-action="clicked article page checklist banner test 2 old version" data-track-label="link" href="https://beta.springernature.com/pre-submission?journalId=401" data-test="article-checklist-banner-link"> <span class="app-card-service__link-text">Use our pre-submission checklist</span> <svg class="app-card-service__link-icon" aria-hidden="true" focusable="false"><use xlink:href="#icon-eds-i-arrow-right-small"></use></svg> </a> <p class="app-card-service__description">Avoid common mistakes on your manuscript.</p> </div> <div class="app-card-service__icon-container"> <svg class="app-card-service__icon" aria-hidden="true" focusable="false"> <use xlink:href="#icon-eds-i-clipboard-check-medium"></use> </svg> </div> </div> <div class="main-content"> <section data-title="Introduction"><div class="c-article-section" id="Sec1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec1">Introduction</h2><div class="c-article-section__content" id="Sec1-content"><p>Abnormal tau accumulation is the common neuropathological feature of a group of neurodegenerative disorders called tauopathies. While Alzheimer’s disease (AD) is the most common tauopathy, progressive supranuclear palsy (PSP) is the most common primary amyloid-independent tauopathy, estimated to affect five in every 100,000 people although recent studies have shown a higher incidence in aged populations [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 16" title="Boxer AL, Yu JT, Golbe LI, Litvan I, Lang AE, Hoglinger GU (2017) Advances in progressive supranuclear palsy: new diagnostic criteria, biomarkers, and therapeutic approaches. Lancet Neurol 16:552–563. 
 https://doi.org/10.1016/S1474-4422(17)30157-6
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR16" id="ref-link-section-d390719442e929">16</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 29" title="Evidente VG, Adler CH, Sabbagh MN, Connor DJ, Hentz JG, Caviness JN et al (2011) Neuropathological findings of PSP in the elderly without clinical PSP: possible incidental PSP? Parkinsonism Relat Disord 17:365–371. 
 https://doi.org/10.1016/j.parkreldis.2011.02.017
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR29" id="ref-link-section-d390719442e932">29</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 76" title="Lyons S, Trepel D, Lynch T, Walsh R, O’Dowd S (2023) The prevalence and incidence of progressive supranuclear palsy and corticobasal syndrome: a systematic review and meta-analysis. J Neurol 270:4451–4465. 
 https://doi.org/10.1007/s00415-023-11791-2
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR76" id="ref-link-section-d390719442e935">76</a>]. On the cellular level, PSP is characterized histopathologically by deposition of abnormal hyperphosphorylated tau (p-tau) in neurons and glia predominantly in the basal ganglia and brainstem [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 24" title="Dickson DW, Ahmed Z, Algom AA, Tsuboi Y, Josephs KA (2010) Neuropathology of variants of progressive supranuclear palsy. Curr Opin Neurol 23:394–400. 
 https://doi.org/10.1097/WCO.0b013e32833be924
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR24" id="ref-link-section-d390719442e938">24</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 26" title="Dickson DW, Rademakers R, Hutton ML (2007) Progressive supranuclear palsy: pathology and genetics. Brain Pathol 17:74–82. 
 https://doi.org/10.1111/j.1750-3639.2007.00054.x
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR26" id="ref-link-section-d390719442e941">26</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Forrest SL, Kril JJ, Halliday GM (2019) Cellular and regional vulnerability in frontotemporal tauopathies. Acta Neuropathol 138:705–727. 
 https://doi.org/10.1007/s00401-019-02035-7
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR33" id="ref-link-section-d390719442e945">33</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 49" title="Hauw JJ, Daniel SE, Dickson D, Horoupian DS, Jellinger K, Lantos PL et al (1994) Preliminary NINDS neuropathologic criteria for Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy). Neurology 44:2015–2019. 
 https://doi.org/10.1212/wnl.44.11.2015
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR49" id="ref-link-section-d390719442e948">49</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 73" title="Litvan I, Hauw JJ, Bartko JJ, Lantos PL, Daniel SE, Horoupian DS et al (1996) Validity and reliability of the preliminary NINDS neuropathologic criteria for progressive supranuclear palsy and related disorders. J Neuropathol Exp Neurol 55:97–105. 
 https://doi.org/10.1097/00005072-199601000-00010
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR73" id="ref-link-section-d390719442e951">73</a>]. Characteristic neuropathologic features are neuronal loss, tau-positive pre-tangles and neurofibrillary tangles (NFTs), neuropil threads, oligodendroglial coiled bodies, and morphologically distinct tufted astrocytes, a hallmark feature of PSP [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 50" title="Hauw JJ, Verny M, Delaere P, Cervera P, He Y, Duyckaerts C (1990) Constant neurofibrillary changes in the neocortex in progressive supranuclear palsy. Basic differences with Alzheimer’s disease and aging. Neurosci Lett 119:182–186. 
 https://doi.org/10.1016/0304-3940(90)90829-x
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR50" id="ref-link-section-d390719442e954">50</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 101" title="Roemer SF, Grinberg LT, Crary JF, Seeley WW, McKee AC, Kovacs GG et al (2022) Rainwater charitable foundation criteria for the neuropathologic diagnosis of progressive supranuclear palsy. Acta Neuropathol 144:603–614. 
 https://doi.org/10.1007/s00401-022-02479-4
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR101" id="ref-link-section-d390719442e957">101</a>]. Tau pathology in oligodendrocytes forming coiled bodies is a feature in PSP and other tauopathies, including corticobasal degeneration (CBD), argyrophilic grain disease (AGD) and globular glial tauopathy (GGT) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Ahmed Z, Bigio EH, Budka H, Dickson DW, Ferrer I, Ghetti B et al (2013) Globular glial tauopathies (GGT): consensus recommendations. Acta Neuropathol 126:537–544. 
 https://doi.org/10.1007/s00401-013-1171-0
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR2" id="ref-link-section-d390719442e960">2</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 25" title="Dickson DW, Bergeron C, Chin SS, Duyckaerts C, Horoupian D, Ikeda K et al (2002) Office of rare diseases neuropathologic criteria for corticobasal degeneration. J Neuropathol Exp Neurol 61:935–946. 
 https://doi.org/10.1093/jnen/61.11.935
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR25" id="ref-link-section-d390719442e964">25</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 100" title="Rodriguez RD, Grinberg LT (2015) Argyrophilic grain disease: an underestimated tauopathy. Dement Neuropsychol 9:2–8. 
 https://doi.org/10.1590/S1980-57642015DN91000002
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR100" id="ref-link-section-d390719442e967">100</a>]. Recently published PSP neuropathological diagnostic criteria includes neurofibrillary tangles in the globus pallidus, substantia nigra, and subthalamic nucleus, and tufted astrocytes in the peri-Rolandic cortices and putamen [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 101" title="Roemer SF, Grinberg LT, Crary JF, Seeley WW, McKee AC, Kovacs GG et al (2022) Rainwater charitable foundation criteria for the neuropathologic diagnosis of progressive supranuclear palsy. Acta Neuropathol 144:603–614. 
 https://doi.org/10.1007/s00401-022-02479-4
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR101" id="ref-link-section-d390719442e970">101</a>]. Multiple PSP clinical subtypes and stages are distinguished by neuroanatomic distribution of tau pathology [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 62" title="Kovacs GG, Lukic MJ, Irwin DJ, Arzberger T, Respondek G, Lee EB et al (2020) Distribution patterns of tau pathology in progressive supranuclear palsy. Acta Neuropathol 140:99–119. 
 https://doi.org/10.1007/s00401-020-02158-2
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR62" id="ref-link-section-d390719442e973">62</a>]. Across subtypes, the subthalamic nucleus is one of the first, and the most severely affected brain regions in this disease [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 125" title="Williams DR, Holton JL, Strand C, Pittman A, de Silva R, Lees AJ et al (2007) Pathological tau burden and distribution distinguishes progressive supranuclear palsy-parkinsonism from Richardson’s syndrome. Brain 130:1566–1576. 
 https://doi.org/10.1093/brain/awm104
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR125" id="ref-link-section-d390719442e976">125</a>]. Mechanisms underlying PSP progression are unclear [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 62" title="Kovacs GG, Lukic MJ, Irwin DJ, Arzberger T, Respondek G, Lee EB et al (2020) Distribution patterns of tau pathology in progressive supranuclear palsy. Acta Neuropathol 140:99–119. 
 https://doi.org/10.1007/s00401-020-02158-2
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR62" id="ref-link-section-d390719442e979">62</a>]. Understanding the molecular changes occurring in vulnerable cell types is important to identify candidate mechanistic drivers of PSP pathology, novel therapeutic targets, and both disease-specific pathways as well as common pathogenic mechanisms of tau-mediated neurodegeneration.</p><p>PSP is largely a sporadic disease, with rare reported cases of autosomal dominant mutations in the <i>MAPT</i> gene causing a PSP-like syndrome [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 36" title="Fujioka S, Sanchez Contreras MY, Strongosky AJ, Ogaki K, Whaley NR, Tacik PM et al (2015) Three sib-pairs of autopsy-confirmed progressive supranuclear palsy. Parkinsonism Relat Disord 21:101–105. 
 https://doi.org/10.1016/j.parkreldis.2014.10.028
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR36" id="ref-link-section-d390719442e988">36</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 37" title="Fujioka S, Van Gerpen JA, Uitti RJ, Dickson DW, Wszolek ZK (2014) Familial progressive supranuclear palsy: a literature review. Neurodegener Dis 13:180–182. 
 https://doi.org/10.1159/000354975
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR37" id="ref-link-section-d390719442e991">37</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 102" title="Rojo A, Pernaute RS, Fontan A, Ruiz PG, Honnorat J, Lynch T et al (1999) Clinical genetics of familial progressive supranuclear palsy. Brain 122(Pt 7):1233–1245. 
 https://doi.org/10.1093/brain/122.7.1233
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR102" id="ref-link-section-d390719442e994">102</a>]. Genome wide association studies (GWAS) have identified a common haplotype in the 17q21.31 <i>MAPT</i> locus as the major genetic risk factor [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Chen JA, Chen Z, Won H, Huang AY, Lowe JK, Wojta K et al (2018) Joint genome-wide association study of progressive supranuclear palsy identifies novel susceptibility loci and genetic correlation to neurodegenerative diseases. Mol Neurodegener 13:41. 
 https://doi.org/10.1186/s13024-018-0270-8
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR20" id="ref-link-section-d390719442e1001">20</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 53" title="Hoglinger GU, Melhem NM, Dickson DW, Sleiman PM, Wang LS, Klei L et al (2011) Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet 43:699–705. 
 https://doi.org/10.1038/ng.859
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR53" id="ref-link-section-d390719442e1004">53</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 104" title="Sanchez-Contreras MY, Kouri N, Cook CN, Serie DJ, Heckman MG, Finch NA et al (2018) Replication of progressive supranuclear palsy genome-wide association study identifies SLCO1A2 and DUSP10 as new susceptibility loci. Mol Neurodegener 13:37. 
 https://doi.org/10.1186/s13024-018-0267-3
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR104" id="ref-link-section-d390719442e1007">104</a>]. The relationship between this genetic risk and disease pathogenesis remains unclear but likely stems from differences in <i>MAPT</i> expression and splicing. Several PSP-associated risk alleles outside of the <i>MAPT</i> locus have been identified, including single nucleotide polymorphisms (SNPs) near <i>STX6</i>, <i>MOBP</i> and <i>EIF2AK3</i> [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Chen JA, Chen Z, Won H, Huang AY, Lowe JK, Wojta K et al (2018) Joint genome-wide association study of progressive supranuclear palsy identifies novel susceptibility loci and genetic correlation to neurodegenerative diseases. Mol Neurodegener 13:41. 
 https://doi.org/10.1186/s13024-018-0270-8
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR20" id="ref-link-section-d390719442e1026">20</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 53" title="Hoglinger GU, Melhem NM, Dickson DW, Sleiman PM, Wang LS, Klei L et al (2011) Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet 43:699–705. 
 https://doi.org/10.1038/ng.859
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR53" id="ref-link-section-d390719442e1029">53</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 104" title="Sanchez-Contreras MY, Kouri N, Cook CN, Serie DJ, Heckman MG, Finch NA et al (2018) Replication of progressive supranuclear palsy genome-wide association study identifies SLCO1A2 and DUSP10 as new susceptibility loci. Mol Neurodegener 13:37. 
 https://doi.org/10.1186/s13024-018-0267-3
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR104" id="ref-link-section-d390719442e1032">104</a>]. <i>EIF2AK3</i> encodes the endoplasmic reticulum (ER) membrane protein, protein kinase R-like ER kinase (PERK), a stress sensor in the unfolded protein response (UPR), which maintains cellular homeostasis under conditions of protein folding disturbances [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 105" title="Scheper W, Hoozemans JJ (2015) The unfolded protein response in neurodegenerative diseases: a neuropathological perspective. Acta Neuropathol 130:315–331. 
 https://doi.org/10.1007/s00401-015-1462-8
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR105" id="ref-link-section-d390719442e1039">105</a>]. PERK activation phosphorylates eukaryotic translation initiation factor 2 alpha (eIF2α), which is a key component of the integrated stress response (ISR), a common adaptive pathway for restoring cellular homeostasis by inhibiting mRNA translation and protein synthesis [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 22" title="Costa-Mattioli M, Walter P (2020) The integrated stress response: from mechanism to disease. Science. 
 https://doi.org/10.1126/science.aat5314
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR22" id="ref-link-section-d390719442e1042">22</a>]. The UPR has been shown to be involved in multiple neurodegenerative diseases including PSP [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 54" title="Hoozemans JJ, van Haastert ES, Nijholt DA, Rozemuller AJ, Eikelenboom P, Scheper W (2009) The unfolded protein response is activated in pretangle neurons in Alzheimer’s disease hippocampus. Am J Pathol 174:1241–1251. 
 https://doi.org/10.2353/ajpath.2009.080814
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR54" id="ref-link-section-d390719442e1045">54</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 55" title="Hoozemans JJ, van Haastert ES, Nijholt DA, Rozemuller AJ, Scheper W (2012) Activation of the unfolded protein response is an early event in Alzheimer’s and Parkinson’s disease. Neurodegener Dis 10:212–215. 
 https://doi.org/10.1159/000334536
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR55" id="ref-link-section-d390719442e1048">55</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 84" title="Nijholt DA, van Haastert ES, Rozemuller AJ, Scheper W, Hoozemans JJ (2012) The unfolded protein response is associated with early tau pathology in the hippocampus of tauopathies. J Pathol 226:693–702. 
 https://doi.org/10.1002/path.3969
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR84" id="ref-link-section-d390719442e1051">84</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 115" title="Stutzbach LD, Xie SX, Naj AC, Albin R, Gilman S, Group PSPGS et al (2013) The unfolded protein response is activated in disease-affected brain regions in progressive supranuclear palsy and Alzheimer’s disease. Acta Neuropathol Commun 1:31. 
 https://doi.org/10.1186/2051-5960-1-31
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR115" id="ref-link-section-d390719442e1054">115</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 121" title="Unterberger U, Hoftberger R, Gelpi E, Flicker H, Budka H, Voigtlander T (2006) Endoplasmic reticulum stress features are prominent in Alzheimer disease but not in prion diseases in vivo. J Neuropathol Exp Neurol 65:348–357. 
 https://doi.org/10.1097/01.jnen.0000218445.30535.6f
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR121" id="ref-link-section-d390719442e1058">121</a>]. Previous bulk transcriptomic analyses using cortical and cerebellar autopsy PSP brain tissue identified transcriptional changes that potentially drive distinct cell-specific tau aggregation [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 7" title="Allen M, Wang X, Serie DJ, Strickland SL, Burgess JD, Koga S et al (2018) Divergent brain gene expression patterns associate with distinct cell-specific tau neuropathology traits in progressive supranuclear palsy. Acta Neuropathol 136:709–727. 
 https://doi.org/10.1007/s00401-018-1900-5
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR7" id="ref-link-section-d390719442e1061">7</a>]. This dataset also identified a positive association of NFTs with synaptic genes and tufted astrocytes with microglial gene-enriched immune networks. This study implicates diverse molecular mechanisms underlying cell-type-specific vulnerability to tau aggregation and degeneration. However, the extent to which this represents differences in the relative abundance of cells or cell-type-specific gene expression changes is challenging to determine with bulk transcriptomic data.</p><p>Recent studies in post-mortem brain tissue using single-cell sequencing have begun to elucidate cell-type-specific changes in different neurodegenerative diseases including AD, Parkinson’s disease (PD) and Huntington’s disease (HD) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Al-Dalahmah O, Sosunov AA, Shaik A, Ofori K, Liu Y, Vonsattel JP et al (2020) Single-nucleus RNA-seq identifies Huntington disease astrocyte states. Acta Neuropathol Commun 8:19. 
 https://doi.org/10.1186/s40478-020-0880-6
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR4" id="ref-link-section-d390719442e1067">4</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 42" title="Grubman A, Chew G, Ouyang JF, Sun G, Choo XY, McLean C et al (2019) A single-cell atlas of entorhinal cortex from individuals with Alzheimer’s disease reveals cell-type-specific gene expression regulation. Nat Neurosci 22:2087–2097. 
 https://doi.org/10.1038/s41593-019-0539-4
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR42" id="ref-link-section-d390719442e1070">42</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 57" title="Kamath T, Abdulraouf A, Burris SJ, Langlieb J, Gazestani V, Nadaf NM et al (2022) Single-cell genomic profiling of human dopamine neurons identifies a population that selectively degenerates in Parkinson’s disease. Nat Neurosci 25:588–595. 
 https://doi.org/10.1038/s41593-022-01061-1
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR57" id="ref-link-section-d390719442e1073">57</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 69" title="Leng K, Li E, Eser R, Piergies A, Sit R, Tan M et al (2021) Molecular characterization of selectively vulnerable neurons in Alzheimer’s disease. Nat Neurosci 24:276–287. 
 https://doi.org/10.1038/s41593-020-00764-7
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR69" id="ref-link-section-d390719442e1076">69</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 77" title="Mathys H, Davila-Velderrain J, Peng Z, Gao F, Mohammadi S, Young JZ et al (2019) Single-cell transcriptomic analysis of Alzheimer’s disease. Nature 570:332–337. 
 https://doi.org/10.1038/s41586-019-1195-2
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR77" id="ref-link-section-d390719442e1079">77</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 85" title="Otero-Garcia M, Mahajani SU, Wakhloo D, Tang W, Xue YQ, Morabito S et al (2022) Molecular signatures underlying neurofibrillary tangle susceptibility in Alzheimer’s disease. Neuron 110(2929–2948):e2928. 
 https://doi.org/10.1016/j.neuron.2022.06.021
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR85" id="ref-link-section-d390719442e1083">85</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 110" title="Smajic S, Prada-Medina CA, Landoulsi Z, Ghelfi J, Delcambre S, Dietrich C et al (2022) Single-cell sequencing of human midbrain reveals glial activation and a Parkinson-specific neuronal state. Brain 145:964–978. 
 https://doi.org/10.1093/brain/awab446
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR110" id="ref-link-section-d390719442e1086">110</a>]. Here, we characterized the transcriptional changes and cellular diversity of the subthalamic nucleus and surrounding regions in PSP and clinically normal control brains using droplet based single-nucleus RNA sequencing (snRNA-seq), a massively parallel single-nucleus sequencing method. We focused our analysis on neurons, astrocytes and oligodendrocytes, the cell types most vulnerable to toxic tau accumulation in PSP, although significant gene expression differences were identified in all cell populations. We observed unique and shared expression profiles in vulnerable cell types, identified EIF2 signaling and other stress pathways as highly dysregulated, and histologically validated eIF2α activation in neurofibrillary and glial tau inclusions in PSP vulnerable brain regions. Our findings support the hypothesis that adaptive stress pathways play a mechanistic role in PSP pathogenesis and highlight the importance of combining single-nucleus molecular data with rigorous neuropathological target validation.</p></div></div></section><section data-title="Methods"><div class="c-article-section" id="Sec2-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec2">Methods</h2><div class="c-article-section__content" id="Sec2-content"><h3 class="c-article__sub-heading" id="Sec3">Human brain tissue samples, nuclei isolation, and single-nucleus RNA sequencing</h3><p>Postmortem fresh frozen autopsy brain tissue and formalin-fixed paraffin-embedded (FFPE) brain tissue from control and autopsy-confirmed PSP cases were obtained from the Neuropathology Brain Bank & Research CoRE at Mount Sinai (New York, NY). Subjects were selected based on their final neuropathological diagnosis at autopsy and were matched according to age, sex, and post-mortem interval (PMI). PSP changes were defined as the presence of p-tau positive tufted astrocytes and neurofibrillary degeneration in regions typically involved in PSP. Exclusion criteria were the presence of significant α-synucleinopathy or TDP-43 proteinopathy. All controls were cognitively normal and negative for established neurodegenerative proteinopathies at the time of autopsy. Extended patient information with co-pathologies, including age-related Alzheimer’s disease neuropathologic change, is provided in Supplementary Data <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/article/10.1007/s00401-024-02823-w#MOESM1">1</a>. Frozen tissue blocks of the diencephalon containing the subthalamic nucleus and adjacent structures (e.g., posterior limb of the internal capsule, zona incerta, inferior portions of thalamic nuclei) were mounted on a cryostat and 30 µm scrolls were cut to ensure equal representation of the entire block. Nuclei were isolated from the scrolls immediately. Tissue scrolls were homogenized in a Dounce homogenizer with Nuclei EZ lysis solution. The suspension from each sample was filtered through a 40um Flowmi™ strainer (Bel-Art), washed, re-filtered, and resuspended in 0.05% BSA PBS containing RNAsin RNAse inhibitor. Nuclear suspension was counted and processed by the Chromium Controller (10 × Genomics) using single Cell 3′ Reagent Kit v2 (Chromium Single Cell 3′ Library & Gel Bead Kit v2, catalog number: 120237; Chromium Single Cell A Chip Kit, 48 runs, catalog number: 120236; 10 × Genomics). Single-nucleus RNA-sequencing (snRNA-seq) was performed by Genewiz and is shared online at Sage Bionetworks (Synapse.org ID: SYN62145232).</p><h3 class="c-article__sub-heading" id="Sec4">Single nucleus RNA-sequencing data processing</h3><p>For each sample, we utilized the Seurat workflow to identify quality cells by mitochondrial rate threshold, ribosomal rate (< 20%) and number of expressed genes (100 < number of expressed genes < 10,000) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 114" title="Stuart T, Butler A, Hoffman P, Hafemeister C, Papalexi E, Mauck WM 3rd et al (2019) Comprehensive integration of single-cell data. Cell 177(1888–1902):e1821. 
 https://doi.org/10.1016/j.cell.2019.05.031
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR114" id="ref-link-section-d390719442e1112">114</a>]. Stringent mitochondrial rate thresholds resulted in loss of neurons in both cases and control groups (Supplementary Fig. 2e–g), therefore mitochondrial rate threshold was first set at < 50% for the data processing step and < 30% for differential expression (see below), followed by high-confidence double removal as inferred by DoubletFinder [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 80" title="McGinnis CS, Murrow LM, Gartner ZJ (2019) DoubletFinder: doublet detection in single-cell RNA sequencing data using artificial nearest neighbors. Cell Syst 8(329–337):e324. 
 https://doi.org/10.1016/j.cels.2019.03.003
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR80" id="ref-link-section-d390719442e1115">80</a>]. The filtered data were normalized by individual sample separately and log-transformed by SCTransform, and the 2000 most variable genes per sample were identified by “FindVariableFeatures()” using Variance Stabilizing Transformation (VST)[<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 43" title="Hafemeister C, Satija R (2019) Normalization and variance stabilization of single-cell RNA-seq data using regularized negative binomial regression. Genome Biol 20:296. 
 https://doi.org/10.1186/s13059-019-1874-1
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR43" id="ref-link-section-d390719442e1118">43</a>]. The sample-wise data was harmonized into a shared embedding space by harmonizing the first 20 principal components (PCs) across the sample-wise single-nuclei transcriptomes with Harmony [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 61" title="Korsunsky I, Millard N, Fan J, Slowikowski K, Zhang F, Wei K et al (2019) Fast, sensitive and accurate integration of single-cell data with Harmony. Nat Methods 16:1289–1296. 
 https://doi.org/10.1038/s41592-019-0619-0
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR61" id="ref-link-section-d390719442e1121">61</a>] (Supplementary Fig. 2b, c). The harmonized data were used to identify the shared nearest neighbor by “FindNeighbors()” with the default k-nearest neighbor (kNN) at 20, followed by Louvain clustering with resolution = 0.8 by “FindClusters()”. Cell type interference was performed by <i>SingleR</i> with a reference dataset of cell type annotated 49,494 single nuclei from Allen Brain Reference Atlas [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 9" title="Aran D, Looney AP, Liu L, Wu E, Fong V, Hsu A et al (2019) Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage. Nat Immunol 20:163–172. 
 https://doi.org/10.1038/s41590-018-0276-y
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR9" id="ref-link-section-d390719442e1128">9</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 82" title="Miller JA, Guillozet-Bongaarts A, Gibbons LE, Postupna N, Renz A, Beller AE et al (2017) Neuropathological and transcriptomic characteristics of the aged brain. Elife. 
 https://doi.org/10.7554/eLife.31126
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR82" id="ref-link-section-d390719442e1131">82</a>]. This yielded 20 clusters with distinct sample compositions, which were assigned to eight major cell types (excitatory neurons, inhibitory neurons, astrocytes, oligodendrocytes, oligodendrocyte precursor cells (OPCs), microglia, endothelial cells, and choroid plexus (ChP) (Supplementary Fig. 2d). The major cell types were validated for most cell clusters through canonical gene expression of known cell type markers: excitatory neurons (<i>NRGN</i> and <i>SLC17A6</i>), inhibitory neurons (<i>GAD1</i>), astrocytes (<i>AQP4</i> and <i>GFAP</i>), microglia (<i>CX3CR1</i> and <i>TYROBP</i>), oligodendrocytes (<i>PLP1</i> and <i>MOBP</i>), OPCs (<i>VCAN</i>), and endothelial cells (<i>FLT1</i>) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 81" title="McKenzie AT, Wang M, Hauberg ME, Fullard JF, Kozlenkov A, Keenan A et al (2018) Brain cell type specific gene expression and co-expression network architectures. Sci Rep 8:8868. 
 https://doi.org/10.1038/s41598-018-27293-5
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR81" id="ref-link-section-d390719442e1169">81</a>]. For the cluster expressing markers for no major cell type, marker genes were manually examined and compared to cell-type-specific gene lists generated from the literature. This resulted in the identification of one additional cell class, choroid plexus (ChP) epithelial cells by expression of <i>ENPP2</i> and <i>SERPINF1</i> [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 88" title="Pellegrini L, Bonfio C, Chadwick J, Begum F, Skehel M, Lancaster MA (2020) Human CNS barrier-forming organoids with cerebrospinal fluid production. Science. 
 https://doi.org/10.1126/science.aaz5626
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR88" id="ref-link-section-d390719442e1178">88</a>] (Supplementary Fig. 2d). Finally, we performed enrichment analysis using Fisher’s Exact Test (FET) on cluster marker signatures with known pathways and functions curated in the Molecular Signature database (MSigDB) using v6.2 collections for BIOCARTA, KEGG, REACTOME, GO-BP, GO-MF, GO-CC, and Hallmark [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 72" title="Liberzon A, Birger C, Thorvaldsdottir H, Ghandi M, Mesirov JP, Tamayo P (2015) The molecular signatures database (MSigDB) hallmark gene set collection. Cell Syst 1:417–425. 
 https://doi.org/10.1016/j.cels.2015.12.004
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR72" id="ref-link-section-d390719442e1181">72</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 116" title="Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA et al (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 102:15545–15550. 
 https://doi.org/10.1073/pnas.0506580102
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR116" id="ref-link-section-d390719442e1185">116</a>]. Significantly enriched pathways were identified by FDR-corrected FET (<i>p </i>value < 0.05). Per sample, we calculated the relative abundance of individual cell clusters and major cell type in each sample, and then calculated the odds ratio (OR) as the standardized enrichment score. The OR distributions between the PSP and control samples were compared by Wilcoxon Rank-sum test (<i>p</i> < 0.05) to evaluate their significant differences in the degrees of enrichments [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 118" title="Szumilas M (2010) Explaining odds ratios. J Can Acad Child Adolesc Psychiatry 19:227–229" href="/article/10.1007/s00401-024-02823-w#ref-CR118" id="ref-link-section-d390719442e1194">118</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 123" title="Vallejo J, Saigusa R, Gulati R, Armstrong Suthahar SS, Suryawanshi V, Alimadadi A et al (2022) Combined protein and transcript single-cell RNA sequencing in human peripheral blood mononuclear cells. BMC Biol 20:193. 
 https://doi.org/10.1186/s12915-022-01382-4
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR123" id="ref-link-section-d390719442e1197">123</a>]. Meta data is provided in Supplementary Data <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/article/10.1007/s00401-024-02823-w#MOESM2">2</a>.</p><h3 class="c-article__sub-heading" id="Sec5">Cell type marker detection</h3><p>We identified cell-type-specific expressions by performing differential expression analysis between each cell cluster and the other clusters. First, individually SCT-normalized data were corrected across different samples for the varying sequencing depths per sample with PrepSCTFindMarkers () [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 43" title="Hafemeister C, Satija R (2019) Normalization and variance stabilization of single-cell RNA-seq data using regularized negative binomial regression. Genome Biol 20:296. 
 https://doi.org/10.1186/s13059-019-1874-1
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR43" id="ref-link-section-d390719442e1211">43</a>]. Then, each cell cluster transcriptome was compared to the rest of the cells by MAST and post-mortem interval (PMI), ribosomal rate, mitochondrial rate, and patient age were included as the latent variables [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 31" title="Finak G, McDavid A, Yajima M, Deng J, Gersuk V, Shalek AK et al (2015) MAST: a flexible statistical framework for assessing transcriptional changes and characterizing heterogeneity in single-cell RNA sequencing data. Genome Biol 16:278. 
 https://doi.org/10.1186/s13059-015-0844-5
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR31" id="ref-link-section-d390719442e1214">31</a>]. Given that the clustering analysis violates the presumed independent and identically distributed data points, stringent thresholds were imposed to identify the significant markers with FDR < 0.05, average fold change > 2, and required greater proportions of PSP cells to express the genes than the control cells [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 59" title="Kiselev VY, Andrews TS, Hemberg M (2019) Challenges in unsupervised clustering of single-cell RNA-seq data. Nat Rev Genet 20:273–282. 
 https://doi.org/10.1038/s41576-018-0088-9
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR59" id="ref-link-section-d390719442e1217">59</a>].</p><h3 class="c-article__sub-heading" id="Sec6">Cell-type-specific differentially expressed genes (DEG)</h3><p>For each cell cluster, we performed differential expression analysis. First, we normalized the gene expression data using SCTransform, then adjusted the normalized data across the varying sequencing depths in different samples with PrepSCTFindMarkers() function in Seurat (v4.1.1) R package [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 43" title="Hafemeister C, Satija R (2019) Normalization and variance stabilization of single-cell RNA-seq data using regularized negative binomial regression. Genome Biol 20:296. 
 https://doi.org/10.1186/s13059-019-1874-1
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR43" id="ref-link-section-d390719442e1228">43</a>]. Within each cell cluster, we performed differential expression analysis between PSP and control cells among low mitochondrial cells (< 30%) by MAST [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 31" title="Finak G, McDavid A, Yajima M, Deng J, Gersuk V, Shalek AK et al (2015) MAST: a flexible statistical framework for assessing transcriptional changes and characterizing heterogeneity in single-cell RNA sequencing data. Genome Biol 16:278. 
 https://doi.org/10.1186/s13059-015-0844-5
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR31" id="ref-link-section-d390719442e1231">31</a>]. We included PMI, ribosomal rate, mitochondrial rate, and patient age at death as latent variables. The significant DEG threshold of nominal <i>p</i> value < 0.05 instead of FDR adjusted <i>p</i> value < 0.05 was used in this discovery analysis to mitigate the low sample size. Candidate pathways and genes were validated in independent replication transcriptomic datasets (see below). We performed enrichment analysis using Fisher’s Exact Test (FET) on DEG signatures with known pathways and functions curated in the Molecular Signature database (MSigDB) using v6.2 collections for BIOCARTA, KEGG, REACTOME, GO-BP, GO-MF, GO-CC, and Hallmark [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 72" title="Liberzon A, Birger C, Thorvaldsdottir H, Ghandi M, Mesirov JP, Tamayo P (2015) The molecular signatures database (MSigDB) hallmark gene set collection. Cell Syst 1:417–425. 
 https://doi.org/10.1016/j.cels.2015.12.004
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR72" id="ref-link-section-d390719442e1240">72</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 116" title="Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA et al (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 102:15545–15550. 
 https://doi.org/10.1073/pnas.0506580102
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR116" id="ref-link-section-d390719442e1244">116</a>]. Significantly enriched pathways were identified by FDR-corrected FET <i>p</i> < 0.05). Finally, differentially regulated pathway activation state analysis was performed with Ingenuity Pathway Analysis (IPA, Qiagen). The average log (fold change) and nominal <i>p</i> value of each significant (<i>p</i> < 0.05) differentially expressed gene was supplied to IPA. For IPA data interpretation and visualization, the following z-score cutoffs were used: for neuronal clusters, – 1 ≥ z-score ≥ 1, for all other clusters, – 2 ≥ z-score ≥ 2. The full pathway lists are provided in Supplementary Data <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/article/10.1007/s00401-024-02823-w#MOESM4">4</a>. Gene set enrichment analysis in major cell types was performed using a list (Supplementary Data <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/article/10.1007/s00401-024-02823-w#MOESM5">5</a>) compiled from Park et al. 2023 and IPA to identify EIF2-related enrichment [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 63" title="Kramer A, Green J, Pollard J Jr, Tugendreich S (2014) Causal analysis approaches in ingenuity pathway analysis. Bioinformatics 30:523–530. 
 https://doi.org/10.1093/bioinformatics/btt703
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR63" id="ref-link-section-d390719442e1263">63</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 87" title="Park G, Xu K, Chea L, Kim K, Safarta L, Song KH et al (2023) Neurodegeneration risk factor, EIF2AK3 (PERK), influences tau protein aggregation. J Biol Chem 299:102821. 
 https://doi.org/10.1016/j.jbc.2022.102821
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR87" id="ref-link-section-d390719442e1266">87</a>].</p><h3 class="c-article__sub-heading" id="Sec7">Validation of gene expression and pathway enrichment</h3><p>We used a recently released publicly available resource [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 83" title="Min Y, Wang X, Is O, Patel TA, Gao J, Reddy JS et al (2023) Cross species systems biology discovers glial DDR2, STOM, and KANK2 as therapeutic targets in progressive supranuclear palsy. Nat Commun 14:6801. 
 https://doi.org/10.1038/s41467-023-42626-3
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR83" id="ref-link-section-d390719442e1278">83</a>] containing single nucleus RNA-sequencing data from PSP and control brain tissue (<i>n</i> = 34) from the temporal cortex. These data are available via the interactive application tool <i>PSP RNAseq Atlas</i> (<a href="https://rtools.mayo.edu/PSP_RNAseq_Atlas/">https://rtools.mayo.edu/PSP_RNAseq_Atlas/</a>). Summary statistics by major cell type for all genes from our EIF2-related enrichment signature were analyzed using the MAST log fold-change (logFC) values (Supplementary Data <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/article/10.1007/s00401-024-02823-w#MOESM5">5</a>). Additionally, differentially expressed genes from this dataset were analyzed using IPA with cutoff of FDR < 0.1 (Supplementary Data <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/article/10.1007/s00401-024-02823-w#MOESM6">6</a>).</p><h3 class="c-article__sub-heading" id="Sec8">Bulk RNA-seq analysis</h3><p>The progressive supranuclear palsy (PSP) RNA-seq data (Synapse ID: SYN3163039) was obtained from synapse.org and reanalyzed as recently reported [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 98" title="Ressler HW, Humphrey J, Vialle RA, Babrowicz B, Kandoi S, Raj T et al (2024) MAPT haplotype-associated transcriptomic changes in progressive supranuclear palsy. Acta Neuropathol Commun 12:135. 
 https://doi.org/10.1186/s40478-024-01839-3
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR98" id="ref-link-section-d390719442e1309">98</a>]. Briefly, RNA-seq data from the cerebellum and temporal cortex from PSP cases (<i>n</i> = 84) and controls (<i>n</i> = 80) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 6" title="Allen M, Burgess JD, Ballard T, Serie D, Wang X, Younkin CS et al (2016) Gene expression, methylation and neuropathology correlations at progressive supranuclear palsy risk loci. Acta Neuropathol 132:197–211. 
 https://doi.org/10.1007/s00401-016-1576-7
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR6" id="ref-link-section-d390719442e1318">6</a>] were processed using RAPiD-nf [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 108" title="Shah H, CW Y, Castellanos R, Pandya C, Giles Z (2015) RAPiD—an agile and dependable RNA-Seq framework. The 65th annual meeting of the American society of human genetics, City" href="/article/10.1007/s00401-024-02823-w#ref-CR108" id="ref-link-section-d390719442e1321">108</a>], a pipeline in the NextFlow framework that uses Trimmomatic (version 0.36) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 15" title="Bolger AM, Lohse M, Usadel B (2014) Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 30:2114–2120. 
 https://doi.org/10.1093/bioinformatics/btu170
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR15" id="ref-link-section-d390719442e1325">15</a>], STAR (version 2.7a) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 27" title="Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S et al (2013) STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29:15–21. 
 https://doi.org/10.1093/bioinformatics/bts635
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR27" id="ref-link-section-d390719442e1328">27</a>], FASTQC (version 0.11.8) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 8" title="Andrews S (2010) FastQC: a quality control tool for high throughput sequence data 
 http://www.bioinformatics.babraham.ac.uk/projects/fastqc
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR8" id="ref-link-section-d390719442e1331">8</a>], featureCounts (version 1.3.1) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 71" title="Liao Y, Smyth GK, Shi W (2014) featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 30:923–930. 
 https://doi.org/10.1093/bioinformatics/btt656
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR71" id="ref-link-section-d390719442e1334">71</a>], and Picard (version 2.20.0) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 56" title="Institute B (2018) Picard tools - by broad institute 
 https://broadinstitute.github.io/picard/
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR56" id="ref-link-section-d390719442e1337">56</a>]. RSEM (version 1.3.1) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 70" title="Li B, Dewey CN (2011) RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. Bmc Bioinform 12:323. 
 https://doi.org/10.1186/1471-2105-12-323
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR70" id="ref-link-section-d390719442e1340">70</a>] was used for differential gene expression. The gene expression matrix was normalized and transformed using the limma::voom() [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 67" title="Law CW, Chen Y, Shi W, Smyth GK (2014) voom: precision weights unlock linear model analysis tools for RNA-seq read counts. Genome Biol 15:R29. 
 https://doi.org/10.1186/gb-2014-15-2-r29
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR67" id="ref-link-section-d390719442e1344">67</a>]. Covariates were selected to minimize expression differences. Clinical and technical variables from Picard were combined and correlated using variancePartition [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 52" title="Hoffman GE, Schadt EE (2016) variancePartition: interpreting drivers of variation in complex gene expression studies. BMC Bioinformatics 17:483. 
 https://doi.org/10.1186/s12859-016-1323-z
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR52" id="ref-link-section-d390719442e1347">52</a>]. The final variables included as covariates were RNA integrity number (RIN), percent duplicate reads, mean insert size, age, sex, and case–control status. Differential gene expression (DGE) analysis was performed using limma [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 79" title="McCarthy DJ, Smyth GK (2009) Testing significance relative to a fold-change threshold is a TREAT. Bioinformatics 25:765–771. 
 https://doi.org/10.1093/bioinformatics/btp053
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR79" id="ref-link-section-d390719442e1350">79</a>]. Statistics were computed using the treat method [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 67" title="Law CW, Chen Y, Shi W, Smyth GK (2014) voom: precision weights unlock linear model analysis tools for RNA-seq read counts. Genome Biol 15:R29. 
 https://doi.org/10.1186/gb-2014-15-2-r29
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR67" id="ref-link-section-d390719442e1353">67</a>].</p><h3 class="c-article__sub-heading" id="Sec9">Immunohistochemistry</h3><p>Formalin-fixed paraffin-embedded (FFPE) tissue sections (5 μm) from blocks containing the basal ganglia (i.e., substantia nigra, putamen, globus pallidus, caudate, subthalamic nucleus), thalamus, Peri-Rolandic cortices, cerebellum containing the dentate nucleus and visual cortex were mounted onto positively charged slides, and baked overnight at 70˚ C. Sections were stained with Luxol fast blue counterstained with hematoxylin and eosin (LHE) on a Leica X Autostainer (Leica Biosystems, Wetzlar, Germany). Immunohistochemistry (IHC) using an antibody targeting phosphorylated tau (AT8, pSer202/pThr205, 1:1000, Thermo Scientific MN1020) was performed on the Ventana Benchmark XT and Ventana Discovery Ultra automatic staining platforms (Ventana Medical Systems, Oro Valley, AZ) according to manufacturer’s instructions with reagents and antibodies acquired from the same lot and positive and negative batch controls. Sections were boiled in CC1 (citric acid buffer, Roche Diagnostics, Basel Switzerland) for 1 h (pH 6) for antigen retrieval, followed by primary antibody incubation for 36 min and visualized using the Ultraview detection kit (Roche Diagnostics) followed by 3,3’-diaminobenzidine (DAB). IHC using antibodies targeting phosphorylated peIF2α (pSer51, 1:1000, Millipore Sigma SAB4504388), and phosphorylated tau (AT8, pSer202/pThr205, 1:1000, Thermo Scientific MN1020) Biosystems, Wetzlar, Germany) was performed on the Leica Bond Rx automatic staining platform according to the manufacturer’s instructions with reagents and antibodies acquired from the same lot and positive and negative batch controls. Heat-induced epitope retrieval (HIER) was performed with EDTA-based pH 6 epitope retrieval solution (Leica Biosystems, Wetzlar, Germany) followed by primary antibody incubation for 20 min and DAB for visualization. For slides that were double labeled, both DAB and alkaline phosphatase were used for visualization. All slides were counterstained with hematoxylin and cover slipped. Slides were imaged using an Aperio Versa 8 (Leica Biosystems, Wetzlar, Germany) and NanoZoomer S210 (Hamamatsu, Shizuoka, Japan) digital slide scanner.</p><h3 class="c-article__sub-heading" id="Sec10">Semiquantitative and digital quantitative histopathologic assessments</h3><p>Positive peIF2α staining was reviewed by an expert neuropathologist, and the cytoplasmic granules with vacuolar features were deemed to be incompatible with lipofuscin pigment and consistent with previous reports of positive staining features [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 115" title="Stutzbach LD, Xie SX, Naj AC, Albin R, Gilman S, Group PSPGS et al (2013) The unfolded protein response is activated in disease-affected brain regions in progressive supranuclear palsy and Alzheimer’s disease. Acta Neuropathol Commun 1:31. 
 https://doi.org/10.1186/2051-5960-1-31
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR115" id="ref-link-section-d390719442e1372">115</a>]. All cases were analyzed using Aperio ImageScope software (versions 9 and 12.3, Leica Biosystems). Neuroanatomical regions were manually segmented on LHE-stained whole slide images and transferred to p-tau (AT8) and peIF2α immunostained sections (Supplementary Fig. 6). For each brain region except the subthalamic nucleus, a 4 mm<sup>2</sup> region was annotated within each neuroanatomical region. Due to the elongated shape and disease-related atrophy of the subthalamic nucleus, the entire region was annotated and normalized to mm<sup>2</sup>. Hyperphosphorylated tau (AT8) burden was semi-quantitatively scored from 0 to 3 (0 = none, 1 = rare, 2 = moderate, 3 = severe) for neuropil threads, neuronal, and glial tau burden according to the Braak criteria [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 5" title="Alafuzoff I, Arzberger T, Al-Sarraj S, Bodi I, Bogdanovic N, Braak H et al (2008) Staging of neurofibrillary pathology in Alzheimer’s disease: a study of the BrainNet Europe consortium. Brain Pathol 18:484–496. 
 https://doi.org/10.1111/j.1750-3639.2008.00147.x
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR5" id="ref-link-section-d390719442e1379">5</a>]. For digital quantitative assessment of tau burden, the Aperio positive pixel count algorithm (version 9) was run in the same 4 mm<sup>2</sup> region using DAB intensity parameters set on the batch control. Total positive pixel values were automatically generated and normalized to total number of pixels detected. For peIF2α quantification, in each brain region the number of peIF2α-positive cells was manually counted in the 4 mm<sup>2</sup> annotation or the entire subthalamic nucleus and normalized to the number of positive cells per mm<sup>2</sup>. Phospo-eIF2α counts were scaled to semiquantitative scores from 0 ( – ) to 3 (+ + +), 0 = no positive cells, 1 = less than 1 positive cell/mm<sup>2</sup>, 2 = less than 2 positive cell/mm<sup>2</sup>, 3 = more than 2 positive cell/mm<sup>2</sup>.</p><h3 class="c-article__sub-heading" id="Sec11">Immunofluorescence microscopy</h3><p>Multiplex immunofluorescence using antibodies targeting peIF2α (pSer51, Millipore Sigma SAB4504388), phosphorylated tau (AT8, pSer202/pThr205, Thermo Scientific MN1020), ALDH1L1 (Abcam, ab190298), and DAPI was performed on the Leica Bond Rx according to manufacturer’s instructions. Secondary antibodies conjugated to Alexa Fluor 488, 594, and 647 fluorophores were used. Slides were imaged on a Zeiss AxioImager Z2M.</p><h3 class="c-article__sub-heading" id="Sec12">Statistics</h3><p>Phospo-eIF2α counts across neuroanatomical regions were compared between PSP and control groups using Fishers exact test (FET). Correlations between peIF2α, semiquantitative tau burden and positive pixel tau burden were analyzed using Pearson’s test. All analysis was performed using GraphPad Prism (version 9.4.0, La Jolla, CA) with significant <i>p</i> value set at < 0.05.</p></div></div></section><section data-title="Results"><div class="c-article-section" id="Sec13-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec13">Results</h2><div class="c-article-section__content" id="Sec13-content"><h3 class="c-article__sub-heading" id="Sec14">Single-nucleus analysis identifies major and novel cell populations</h3><p>To investigate the cellular diversity and cell-type-specific disease-related gene expression changes occurring in PSP, we isolated nuclei from the subthalamic nucleus and surrounding regions from three PSP cases and three age-matched controls (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/article/10.1007/s00401-024-02823-w#Tab1">1</a>, Supplementary Data <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/article/10.1007/s00401-024-02823-w#MOESM1">1</a>). PSP disease stage was assessed by semiquantitative evaluation of immunohistochemically stained formalin fixed paraffin embedded (FFPE) tissue from the contralateral subthalamic nucleus and adjacent regions using antisera recognizing hyperphosphorylated tau (p-tau) at Ser202/Thr205 (AT8). Staining confirmed neuropathological diagnosis with varying tau burdens in the PSP cases, spanning the progression of PSP-type tau pathology (Supplementary Fig. 1). Semi-quantitative assessment of disease severity measured neurofibrillary tangles (NFTs), neuropil threads (NT), and glial fibrillary tangles (GFT) including tufted astrocytes and coiled bodies in the PSP cases (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/article/10.1007/s00401-024-02823-w#Tab1">1</a>). PSP3 had the overall highest tau burden, with severe NFT, NT, and GFT burden representing the late stage of disease progression. Both PSP2 and PSP3 had a higher glial tau burden than PSP1, which had an overall lower tau burden and was likely in the early stage of disease.</p><div class="c-article-table" data-test="inline-table" data-container-section="table" id="table-1"><figure><figcaption class="c-article-table__figcaption"><b id="Tab1" data-test="table-caption">Table 1 SnRNAseq Patient data</b></figcaption><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="table-link" data-track="click" data-track-action="view table" data-track-label="button" rel="nofollow" href="/article/10.1007/s00401-024-02823-w/tables/1" aria-label="Full size table 1"><span>Full size table</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>Droplet–based single-nucleus RNA-sequencing (snRNA-seq) was performed on the six samples using the 10X Genomics platform (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02823-w#Fig1">1</a>a). Initial quality control (QC) measures showed that two PSP samples had preferentially higher mitochondrial rates than the controls and retained less than 50% of all cells with the conventional < 10% threshold (Supplementary Data <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/article/10.1007/s00401-024-02823-w#MOESM2">2</a>). As PSP is a neurodegenerative disease with a greater proportion of diseased cells than healthy control samples, we first applied a fixed yet lenient mitochondrial rate threshold across all samples that removes highly compromised cells while allowing the inclusion of diseased cells whose qualities were affected by disease pathology. (Supplementary Fig. 2a). Further filtering for low depths and data harmonization resulted in 50,708 high quality nuclei profiles with a median 1,019 genes detected per nucleus (Supplementary Fig. 2b, c). Of these, 20,322 were PSP nuclei and 30,386 were control nuclei (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/article/10.1007/s00401-024-02823-w#Tab2">2</a>). The overall numbers of QCed cells show a lower proportion of cells from PSP samples remained than controls. Nuclei expression profiles were clustered using Seurat workflow based on the k-nearest neighbor approach and mapped to individual cell types. This yielded 20 cell clusters. Separating the cells by disease status showed that PSP cells both overlap with and segregate from controls across the 20 clusters (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02823-w#Fig1">1</a>b, c)<b>.</b></p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-1" data-title="Fig. 1"><figure><figcaption><b id="Fig1" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 1</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/article/10.1007/s00401-024-02823-w/figures/1" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs00401-024-02823-w/MediaObjects/401_2024_2823_Fig1_HTML.png?as=webp"><img aria-describedby="Fig1" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs00401-024-02823-w/MediaObjects/401_2024_2823_Fig1_HTML.png" alt="figure 1" loading="lazy" width="685" height="860"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-1-desc"><p>Single-nuclei sequencing in progressive supranuclear palsy (PSP) and control post-mortem brain identifies cell-type-specific marker genes. <b>a</b> Schematic of experimental design and snRNA-seq workflow. <b>b</b>, <b>c</b> UMAP projection of cell populations colored by <b>b</b> cell type, and <b>c</b> diagnosis (PSP, red; control, green). The major cell types identified are oligodendrocytes (Oligo1-7), microglia (Micro1, Micro2), astrocytes (Astro1, Astro2), endothelial cells (Endo), neurons marked as excitatory (Exc1-4) or inhibitory (Inh1, Inh2), oligodendrocyte precursor cells (OPC), and choroid-plexus (ChP). <b>d</b> Composition of individual samples by cell clusters. <b>e</b> Composition of each cell cluster by sample. <b>f</b>, <b>g</b> Enrichment score of <b>f</b> individual samples in different cell clusters and <b>g</b> major cell type; <i>x</i>-axis, cell clusters; <i>y</i>-axis, odds ratio (OR) as the enrichment statistics. Asterisks (*) highlight clusters and cell types with significant differences between PSP and controls, Wilcoxon rank-sum test, <i>p</i> < 0.05</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/article/10.1007/s00401-024-02823-w/figures/1" data-track-dest="link:Figure1 Full size image" aria-label="Full size image figure 1" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><div class="c-article-table" data-test="inline-table" data-container-section="table" id="table-2"><figure><figcaption class="c-article-table__figcaption"><b id="Tab2" data-test="table-caption">Table 2 SnRNA-seq QC summary</b></figcaption><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="table-link" data-track="click" data-track-action="view table" data-track-label="button" rel="nofollow" href="/article/10.1007/s00401-024-02823-w/tables/2" aria-label="Full size table 2"><span>Full size table</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>To identify cell type and understand the molecular features and functions that define the clusters, we assigned distinct marker genes for each cluster, compared over-expressed genes within clusters (FDR < 0.05, fold-change > 2, and % expressed within cluster > % expressed in the rest), and examined enriched functions and pathways by gene ontology (GO) analysis (Supplementary Data <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/article/10.1007/s00401-024-02823-w#MOESM2">2</a>). All major cell types (excitatory neurons, inhibitory neurons, astrocytes, oligodendrocytes, microglia, oligodendrocyte precursor cells (OPC), and endothelial cells) were identified within the 20 clusters based on the Allen Brain Reference Atlas previously established cell-type-specific marker genes [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 81" title="McKenzie AT, Wang M, Hauberg ME, Fullard JF, Kozlenkov A, Keenan A et al (2018) Brain cell type specific gene expression and co-expression network architectures. Sci Rep 8:8868. 
 https://doi.org/10.1038/s41598-018-27293-5
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR81" id="ref-link-section-d390719442e2405">81</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 82" title="Miller JA, Guillozet-Bongaarts A, Gibbons LE, Postupna N, Renz A, Beller AE et al (2017) Neuropathological and transcriptomic characteristics of the aged brain. Elife. 
 https://doi.org/10.7554/eLife.31126
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR82" id="ref-link-section-d390719442e2408">82</a>] (Supplementary Fig. 2d). GO enrichment analysis confirmed the enriched functions and pathways of the cluster marker genes were consistent with the biological functions of the assigned cell type (Supplementary Fig. 3).</p><p>In addition to all major cell types, we also identified one novel cluster. This was marked by several choroid plexus epithelial cell genes including <i>CA2</i>, <i>HTR2C</i>, and <i>IGFBP7</i>, and several molecules in cerebrospinal fluid (CSF) secretome such as <i>SERPINF1</i>, <i>AQP1</i>, <i>ENPP2</i>, <i>CLU,</i> and <i>NPC2</i>, therefore this cluster was designated as choroid plexus (ChP) epithelial cells [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 88" title="Pellegrini L, Bonfio C, Chadwick J, Begum F, Skehel M, Lancaster MA (2020) Human CNS barrier-forming organoids with cerebrospinal fluid production. Science. 
 https://doi.org/10.1126/science.aaz5626
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR88" id="ref-link-section-d390719442e2439">88</a>] (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02823-w#Fig1">1</a>b, Supplementary Fig. 2d, Supplementary Data 2). Overall, we obtained 1276 endothelial cells, 4707 microglia, 8150 neurons, 6701 astrocytes, 26,546 oligodendrocytes, 2952 OPCs, and 376 choroid plexus cells.</p><p>To assess whether the proportions of major cell types and subclusters change with disease state, we first calculated the relative abundance of each cell cluster or major cell type belonging to individual PSP and control samples and the per sample cluster composition (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02823-w#Fig1">1</a>d, e). Comparison of the per sample cluster composition shows that across all samples, the majority of cells were glial cells, and particularly oligodendrocytes were the most abundant (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02823-w#Fig1">1</a>d)<b>.</b> This is consistent with the neuroanatomical region targeted, which included a high proportion of white matter (Supplementary Fig. 1a). Then, we calculated the per sample odds ratio (OR) of individual cell clusters and major cell types as a standardized enrichment score, and compared the OR distributions between PSP and healthy control samples (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02823-w#Fig1">1</a>f, g). In non-neuronal cell populations, the proportion of most individual clusters and major cell types were comparable in PSP cases and controls. However, several neuronal cell clusters showed distinct differences in the enrichment patterns in these groups, with three excitatory neuronal clusters (Exc1, Exc3, and Exc4), and one inhibitory neuronal cluster (Inh1) showing significant enrichment in controls suggesting depletion or under-representation in PSP (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02823-w#Fig1">1</a>f). The neuronal clusters with potential neurodegeneration in PSP overexpress <i>CELF2</i> and <i>PEG3</i>, genes which have been shown to induce apoptosis and neuronal death [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 18" title="Broad KD, Curley JP, Keverne EB (2009) Increased apoptosis during neonatal brain development underlies the adult behavioral deficits seen in mice lacking a functional paternally expressed gene 3 (Peg3). Dev Neurobiol 69:314–325. 
 https://doi.org/10.1002/dneu.20702
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR18" id="ref-link-section-d390719442e2471">18</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 66" title="Lai S, Wang Y, Li T, Dong Y, Lin Y, Wang L et al (2022) N6-methyladenosine-mediated CELF2 regulates CD44 alternative splicing affecting tumorigenesis via ERAD pathway in pancreatic cancer. Cell Biosci 12:125. 
 https://doi.org/10.1186/s13578-022-00844-0
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR66" id="ref-link-section-d390719442e2474">66</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 96" title="Relaix F, Wei X, Li W, Pan J, Lin Y, Bowtell DD et al (2000) Pw1/Peg3 is a potential cell death mediator and cooperates with Siah1a in p53-mediated apoptosis. Proc Natl Acad Sci U S A 97:2105–2110. 
 https://doi.org/10.1073/pnas.040378897
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR96" id="ref-link-section-d390719442e2477">96</a>]. The neuronal clusters that were not enriched and with no apparent neurodegeneration in PSP, Ex2 and Inh2, overexpress <i>PPP3CA</i> (PP2B), one of the major phosphatases that directly regulates tau phosphorylation, and <i>ARPP21</i> and <i>ARPP19</i>, genes that mediate protein phosphorylation through cAMP [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 40" title="Gong CX, Shaikh S, Wang JZ, Zaidi T, Grundke-Iqbal I, Iqbal K (1995) Phosphatase activity toward abnormally phosphorylated tau: decrease in Alzheimer disease brain. J Neurochem 65:732–738. 
 https://doi.org/10.1046/j.1471-4159.1995.65020732.x
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR40" id="ref-link-section-d390719442e2490">40</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 92" title="Qian W, Yin X, Hu W, Shi J, Gu J, Grundke-Iqbal I et al (2011) Activation of protein phosphatase 2B and hyperphosphorylation of Tau in Alzheimer’s disease. J Alzheimers Dis 23:617–627. 
 https://doi.org/10.3233/JAD-2010-100987
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR92" id="ref-link-section-d390719442e2493">92</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 94" title="Rahman A, Grundke-Iqbal I, Iqbal K (2006) PP2B isolated from human brain preferentially dephosphorylates Ser-262 and Ser-396 of the Alzheimer disease abnormally hyperphosphorylated tau. J Neural Transm (Vienna) 113:219–230. 
 https://doi.org/10.1007/s00702-005-0313-5
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR94" id="ref-link-section-d390719442e2496">94</a>] (Supplementary Data <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/article/10.1007/s00401-024-02823-w#MOESM2">2</a>)<b>.</b></p><h3 class="c-article__sub-heading" id="Sec15">Differential gene expression analysis identifies dysregulated cellular functions in PSP neurons</h3><p>We then stratified the cells into high and low mitochondrial rate groups using a more strict threshold, which revealed that neuronal subsets, which contain neurofibrillary tangles in PSP, showed predominantly higher proportions of high mitochondrial cells than other major cell types (Supplementary Fig. 2e–g). Therefore, we performed differential gene expression analysis on cells using a 30% threshold cutoff. Differentially expressed genes (DEG) were examined by cell cluster or major cell type, then the major pathways represented by DEGs were identified and compared between PSP and controls using integrated pathway analysis (IPA) (Supplementary Fig. 4, Supplementary Data 3–4)<b>.</b> We first focused on differential gene expression between PSP cases and controls in neurons. Across neuronal clusters, the largest differential gene expression was observed in excitatory neuron clusters Ex1 and Ex3 and inhibitory neuron cluster Inh1 (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02823-w#Fig2">2</a>a)<b>.</b></p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-2" data-title="Fig. 2"><figure><figcaption><b id="Fig2" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 2</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/article/10.1007/s00401-024-02823-w/figures/2" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs00401-024-02823-w/MediaObjects/401_2024_2823_Fig2_HTML.png?as=webp"><img aria-describedby="Fig2" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs00401-024-02823-w/MediaObjects/401_2024_2823_Fig2_HTML.png" alt="figure 2" loading="lazy" width="685" height="716"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-2-desc"><p>Differentially expressed genes (DEGs) and dysregulated pathways in neuronal clusters. <b>a</b> Total numbers of significant upregulated and downregulated genes in excitatory (Ex1, Ex2, Ex3, Ex4) and inhibitory (Inh1, Inh2) neuron populations between PSP and controls. <b>b</b> Volcano plots showing select significant DEGs in individual neuronal clusters. <b>c</b> Heatmap showing 50 selected differentially regulated pathways (z-score ≥ 1 or ≤ – 1) in PSP neuron clusters derived from ingenuity pathway analysis (IPA). Positive or negative scores predict an overall increase or decrease in pathway activity, respectively. <b>d</b> Ten most enriched GO functions and pathways per up- or down-regulated (UP or DN) genes in PSP neurons are shown</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/article/10.1007/s00401-024-02823-w/figures/2" data-track-dest="link:Figure2 Full size image" aria-label="Full size image figure 2" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>The neuronal clusters that were less abundant in PSP (Ex1, Ex3, Ex4, and Inh1) were enriched for genes related to apoptosis, neuronal injury, and several genes and pathways critical to neuronal signaling and function (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02823-w#Fig2">2</a>b, c). These clusters downregulated multiple genes related to apoptosis regulation, including <i>JUND</i>, <i>IFI6</i>, and <i>MTRNR2L12</i>, and overexpressed <i>NEFM</i>, which encodes for a neurofilament protein that is a biomarker of neuronal injury and neurodegeneration [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 132" title="Yuan A, Nixon RA (2021) Neurofilament proteins as biomarkers to monitor neurological diseases and the efficacy of therapies. Front Neurosci 15:689938. 
 https://doi.org/10.3389/fnins.2021.689938
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR132" id="ref-link-section-d390719442e2570">132</a>]. Genes related to neurotransmitter release, neuronal arborization and morphology, such as <i>HRH3</i> and <i>VAMP2</i>, were also downregulated in these clusters [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 129" title="Yan C, Jiang J, Yang Y, Geng X, Dong W (2022) The function of VAMP2 in mediating membrane fusion: an overview. Front Mol Neurosci 15:948160. 
 https://doi.org/10.3389/fnmol.2022.948160
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR129" id="ref-link-section-d390719442e2579">129</a>]. Several genes related to calcium signaling were significantly differentially expressed such as calmodulin (<i>CALM1)</i>, and <i>CALB2,</i> as well as Purkinje cell protein 4 (<i>PCP4)</i>, which regulates calmodulin-mediated signaling and neuronal survival [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 46" title="Harashima S, Wang Y, Horiuchi T, Seino Y, Inagaki N (2011) Purkinje cell protein 4 positively regulates neurite outgrowth and neurotransmitter release. J Neurosci Res 89:1519–1530. 
 https://doi.org/10.1002/jnr.22688
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR46" id="ref-link-section-d390719442e2592">46</a>]. Notably, several pathways related to critical neuronal functions such as calcium signaling, protein kinase A signaling, synaptogenesis signaling, and synaptic long-term potentiation were dysregulated in neuronal clusters, along with apoptosis and senescent pathways (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02823-w#Fig2">2</a>c). Two of these neuronal clusters, Ex1 and Ex3, had reduced <i>MAPT</i> expression (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02823-w#Fig2">2</a>b). Additionally, PSP neurons overexpressed genes involved in iron homeostasis and heavy metal accumulation, including ferritin light chain (<i>FTL), FTH1</i>, and transferrin (<i>Tf</i>) which encode for proteins related to ferritin iron storage, and <i>MT3</i> which binds heavy metals [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 60" title="Koh JY, Lee SJ (2020) Metallothionein-3 as a multifunctional player in the control of cellular processes and diseases. Mol Brain 13:116. 
 https://doi.org/10.1186/s13041-020-00654-w
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR60" id="ref-link-section-d390719442e2614">60</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 68" title="Lee S, Martinez-Valbuena I, de Andrea CE, Villalba-Esparza M, Ilaalagan S, Couto B et al (2023) Cell-specific dysregulation of iron and oxygen homeostasis as a novel pathophysiology in PSP. Ann Neurol 93:431–445. 
 https://doi.org/10.1002/ana.26540
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR68" id="ref-link-section-d390719442e2617">68</a>]. Pathways such as iron uptake and transport and ferroptosis signaling pathway were also enriched in PSP neurons.</p><p>Several genes related to protein translation, topologically incorrect protein degradation, the unfolded protein response, and endoplasmic reticulum (ER) stress including ribosomal, heat shock and chaperone genes were differentially expressed in multiple excitatory neuronal clusters, such as <i>CANX, DNAJB2</i>, <i>MVD</i>, <i>RHBDD2, HSPA1B,</i> and <i>SRP14</i> (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02823-w#Fig2">2</a>b). Increased EIF2 signaling, a target of the ISR and UPR homeostatic stress response, was enriched across neuronal clusters, along with other stress response pathways such as cellular response to hypoxia and heat stress, response to EIF2AK4 to amino acid deficiency, and XBP1 (s) activates chaperone genes (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02823-w#Fig2">2</a>c). PSP excitatory neurons also showed reduced chaperone-mediated autophagy signaling. GO-enrichment analysis also highlights protein localization to the endoplasmic reticulum as an upregulated function in PSP excitatory neurons (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02823-w#Fig2">2</a>d). Overall, these data provide a summary of the gene expression changes and related functional pathways in PSP neurons, highlighting apoptosis, iron homeostasis, EIF2 signaling and stress response pathways as dysregulated cellular functions that may underlie disease-related changes.</p><h3 class="c-article__sub-heading" id="Sec16">Differential gene expression analysis identifies dysregulated cell functions in PSP glial populations</h3><p>We next investigated the cell-type-specific gene expression changes in the glial cells uniquely affected by tau accumulation in PSP, including astrocyte and oligodendrocytes. Our analysis revealed high numbers of differentially expressed genes (DEGs) in PSP oligodendrocyte subclusters (Oligo1, Oligo2, Oligo3) and astrocyte subclusters (Astro1, Astro2) (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02823-w#Fig3">3</a>a). Consistent with the differential gene expression changes and EIF2 activation seen in PSP neurons, several genes related to protein translation, topologically incorrect protein degradation, the unfolded protein response, and ER stress were significantly dysregulated in PSP astrocyte and oligodendrocyte clusters, such as <i>ATF6, DNAJB1, DNAJB2, HSPA1A</i>, <i>HSPB1</i>, <i>SREBF1</i>, <i>ACTB</i>, <i>VEGFA</i> and <i>SRP14</i> as well as several ribosomal genes (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02823-w#Fig3">3</a>b). <i>EIF2AK3</i> expression, which encodes for PERK, was increased in two oligodendrocyte clusters (Oligo1, Oligo5). PSP astrocytes and oligodendrocytes also differentially expressed several UPR genes including PERK-regulated genes <i>ATF3</i>, <i>NUPR1</i>, <i>CEBPB</i>, and <i>GADD45A,</i> and were enriched for several stress response-related pathways such as increased EIF2 signaling, XBP1 (s) activates chaperone genes, cellular response to hypoxia, heat shock protein binding, and the unfolded protein response [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 75" title="Lu PD, Jousse C, Marciniak SJ, Zhang Y, Novoa I, Scheuner D et al (2004) Cytoprotection by pre-emptive conditional phosphorylation of translation initiation factor 2. EMBO J 23:169–179. 
 https://doi.org/10.1038/sj.emboj.7600030
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR75" id="ref-link-section-d390719442e2694">75</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 87" title="Park G, Xu K, Chea L, Kim K, Safarta L, Song KH et al (2023) Neurodegeneration risk factor, EIF2AK3 (PERK), influences tau protein aggregation. J Biol Chem 299:102821. 
 https://doi.org/10.1016/j.jbc.2022.102821
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR87" id="ref-link-section-d390719442e2697">87</a>] (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02823-w#Fig3">3</a>b–d). In addition to dysregulated stress response, PSP astrocytes and oligodendrocytes also had decreased expression of <i>ENO2</i> and <i>PTGDS,</i> which code for proteins with potential neuroprotective and anti-apoptotic functions [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 44" title="Hafner A, Glavan G, Obermajer N, Zivin M, Schliebs R, Kos J (2013) Neuroprotective role of gamma-enolase in microglia in a mouse model of Alzheimer’s disease is regulated by cathepsin X. Aging Cell 12:604–614. 
 https://doi.org/10.1111/acel.12093
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR44" id="ref-link-section-d390719442e2710">44</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 103" title="Sakry D, Yigit H, Dimou L, Trotter J (2015) Oligodendrocyte precursor cells synthesize neuromodulatory factors. PLoS ONE 10:e0127222. 
 https://doi.org/10.1371/journal.pone.0127222
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR103" id="ref-link-section-d390719442e2713">103</a>] (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02823-w#Fig3">3</a>b, c). Both PSP astrocytes and oligodendrocytes were also associated with increased mTOR and apoptosis signaling pathways, and reduced chaperone-mediated autophagy signaling (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02823-w#Fig3">3</a>c).</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-3" data-title="Fig. 3"><figure><figcaption><b id="Fig3" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 3</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/article/10.1007/s00401-024-02823-w/figures/3" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs00401-024-02823-w/MediaObjects/401_2024_2823_Fig3_HTML.png?as=webp"><img aria-describedby="Fig3" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs00401-024-02823-w/MediaObjects/401_2024_2823_Fig3_HTML.png" alt="figure 3" loading="lazy" width="685" height="724"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-3-desc"><p>Differentially expressed genes (DEGs) and regulated pathways in astrocytes and oligodendrocytes. <b>a</b> Total numbers of significant upregulated and downregulated genes in astrocytes (Astro1, Astro2), and oligodendrocytes (Oligo1-7). <b>b</b> Volcano plots showing select significant DEGs in individual glial clusters. <b>c</b> Heatmap showing 50 selected differentially regulated pathways (z-score ≥ 2 or ≤ – 2) in PSP glial clusters derived from ingenuity pathway analysis (IPA). Positive or negative scores predict an overall increase or decrease in pathway activity, respectively. <b>d</b> Top 10 most enriched GO functions and pathways per up- or down-regulated (UP or DN) genes in PSP glia are shown</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/article/10.1007/s00401-024-02823-w/figures/3" data-track-dest="link:Figure3 Full size image" aria-label="Full size image figure 3" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>Many genes that have been previously linked to other neurodegenerative diseases were also differentially expressed in PSP astrocytes and oligodendrocytes (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02823-w#Fig3">3</a>b). <i>MAPT</i> expression was increased in two oligodendrocyte clusters (Oligo1, Oligo5). Both PSP astrocytes and oligodendrocytes overexpressed AD-associated genes apolipoprotein E (<i>ApoE</i>) and clusterin (<i>CLU)</i>, which codes for a chaperone protein involved in several biological events such as cell death [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 35" title="Foster EM, Dangla-Valls A, Lovestone S, Ribe EM, Buckley NJ (2019) Clusterin in Alzheimer’s disease: mechanisms, genetics, and lessons from other pathologies. Front Neurosci 13:164. 
 https://doi.org/10.3389/fnins.2019.00164
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR35" id="ref-link-section-d390719442e2767">35</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 95" title="Raulin AC, Doss SV, Trottier ZA, Ikezu TC, Bu G, Liu CC (2022) ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies. Mol Neurodegener 17:72. 
 https://doi.org/10.1186/s13024-022-00574-4
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR95" id="ref-link-section-d390719442e2771">95</a>]. Additional AD-associated genes were differentially expressed in PSP oligodendrocytes, including increased expression of quinoid dihydropteridine reductase (<i>QDPR)</i> and decreased expression of <i>DHCR24</i>, a gene with cholesterol-synthesizing activity [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 10" title="Bai X, Mai M, Yao K, Zhang M, Huang Y, Zhang W et al (2022) The role of DHCR24 in the pathogenesis of AD: re-cognition of the relationship between cholesterol and AD pathogenesis. Acta Neuropathol Commun 10:35. 
 https://doi.org/10.1186/s40478-022-01338-3
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR10" id="ref-link-section-d390719442e2780">10</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 77" title="Mathys H, Davila-Velderrain J, Peng Z, Gao F, Mohammadi S, Young JZ et al (2019) Single-cell transcriptomic analysis of Alzheimer’s disease. Nature 570:332–337. 
 https://doi.org/10.1038/s41586-019-1195-2
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR77" id="ref-link-section-d390719442e2783">77</a>]. Both PSP astrocytes and oligodendrocytes were also associated with increased activation of pathways related to inflammation, oxidative phosphorylation, and post-translational protein phosphorylation (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02823-w#Fig3">3</a>c).</p><p>In parallel with PSP neurons, iron homeostasis was dysregulated in PSP glia. PSP astrocytes overexpressed many genes involved in iron homeostasis, including <i>CP</i>, <i>FTL</i>, <i>LRP1</i>, and <i>FTH</i>, as well as <i>MT1G</i>, which is involved in cellular response to intracellular metal toxicity [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 60" title="Koh JY, Lee SJ (2020) Metallothionein-3 as a multifunctional player in the control of cellular processes and diseases. Mol Brain 13:116. 
 https://doi.org/10.1186/s13041-020-00654-w
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR60" id="ref-link-section-d390719442e2808">60</a>]. Both PSP astrocytes and oligodendrocytes were also associated with increased ferroptosis signaling pathway or iron uptake and transport, and downregulated genes involved in oxygen homeostasis including alpha and beta hemoglobin (<i>HBA1</i>, <i>HBA2</i>, <i>HBB</i>) (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02823-w#Fig3">3</a>b–d).</p><p>These data provide a summary of the discrete and common gene expression changes and related functional pathways in PSP astrocyte and oligodendrocyte clusters. We highlight EIF2 signaling, ER stress and other dysregulated stress response, iron accumulation and oxygen homeostasis, and other pathways previously linked to neurodegeneration, as potential mechanisms which may underlie cell-type-specific susceptibility to disease pathology in PSP glia.</p><h3 class="c-article__sub-heading" id="Sec17">EIF2 pathway enrichment and validation</h3><p>To further investigate transcriptomic dysregulation of EIF2 signaling in different cell types in PSP, we performed gene set enrichment analysis to look at signatures across major cell types using a list representing EIF2 and ER stress-related genes from IPA and the literature [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 87" title="Park G, Xu K, Chea L, Kim K, Safarta L, Song KH et al (2023) Neurodegeneration risk factor, EIF2AK3 (PERK), influences tau protein aggregation. J Biol Chem 299:102821. 
 https://doi.org/10.1016/j.jbc.2022.102821
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR87" id="ref-link-section-d390719442e2834">87</a>]. We observed significantly enriched EIF2-related DEG signatures in excitatory neurons, microglia, astrocytes, and oligodendrocytes (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02823-w#Fig4">4</a>a, b). To validate our findings, we examined this gene list in a recently reported human post-mortem PSP single cell dataset in the temporal neocortex (<i>n</i> = 34) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 83" title="Min Y, Wang X, Is O, Patel TA, Gao J, Reddy JS et al (2023) Cross species systems biology discovers glial DDR2, STOM, and KANK2 as therapeutic targets in progressive supranuclear palsy. Nat Commun 14:6801. 
 https://doi.org/10.1038/s41467-023-42626-3
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR83" id="ref-link-section-d390719442e2843">83</a>]. In this validation dataset, we also observe EIF2 enrichment across vulnerable cell types, including neurons, astrocytes, and oligodendrocytes (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02823-w#Fig4">4</a>c). Examination of the entire differentially expressed gene lists in tau-vulnerable cell type in this dataset showed enrichment of EIF2 signaling and many pathways related to dysregulated stress response, such as endoplasmic reticulum stress pathway, unfolded protein response, and response of EIF2AK3 (GCN2) to amino acid deficiency (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02823-w#Fig4">4</a>d). We further examined EIF2 transcriptomic signatures in a publically available PSP bulk RNA-seq dataset from the temporal cortex and cerebellum (PSP <i>n</i> = 84, controls <i>n</i> = 80) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 6" title="Allen M, Burgess JD, Ballard T, Serie D, Wang X, Younkin CS et al (2016) Gene expression, methylation and neuropathology correlations at progressive supranuclear palsy risk loci. Acta Neuropathol 132:197–211. 
 https://doi.org/10.1007/s00401-016-1576-7
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR6" id="ref-link-section-d390719442e2859">6</a>]. In both regions, upregulation of EIF2 and ER-stress-related genes were also observed (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02823-w#Fig4">4</a>e, f). These results in independent transcriptional datasets validate our findings that alterations in EIF2 signaling and stress response are prominent in human post-mortem PSP brain in different vulnerable cell subtypes.</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-4" data-title="Fig. 4"><figure><figcaption><b id="Fig4" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 4</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/article/10.1007/s00401-024-02823-w/figures/4" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs00401-024-02823-w/MediaObjects/401_2024_2823_Fig4_HTML.png?as=webp"><img aria-describedby="Fig4" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs00401-024-02823-w/MediaObjects/401_2024_2823_Fig4_HTML.png" alt="figure 4" loading="lazy" width="685" height="596"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-4-desc"><p>EIF2 pathway enrichment in major brain cell types and validation. <b>a</b> FDR-adjusted Fisher’s Exact Test (FET) <i>p</i> value for enrichments of EIF2 signatures in major cell-type-specific DEG signatures (red, up-regulated; blue, down-regulated). <b>b</b> Differential expressions of individual genes in the EIF2 signature. For each cell type (x-axis) across the EIF2 signature genes (y-axis), the dot size represents the proportion of PSP cells expressing the gene, the border color marks significant DEGs (red, up-regulated; blue, down-regulated) by <i>p</i> value < 0.05, and the color shows the average log2(expression fold change) in PSP cells compared to controls. <b>c</b> Differential expression of individual genes in EIF2 signature in major cell types from Min et al. 2023 by FDR < 0.05. <b>d</b> Differentially regulated stress response pathways in PSP clusters from Min et al. 2023 derived from ingenuity pathway analysis (IPA). <b>e</b>, <b>f</b> EIF2 gene expression in PSP temporal cortex and cerebellum from bulk RNA-seq (Allen et al., 2016)</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/article/10.1007/s00401-024-02823-w/figures/4" data-track-dest="link:Figure4 Full size image" aria-label="Full size image figure 4" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><h3 class="c-article__sub-heading" id="Sec18">Activated EIF2 signaling in PSP is associated with tau pathology</h3><p>SnRNA-seq analysis revealed increased EIF2 signaling activation in multiple cell populations vulnerable to tau accumulation in PSP, including neurons, astrocytes, and oligodendrocytes. Given that EIF2 is a component of the ISR, an elaborate signaling pathway activated in a range of both normal and pathological contexts, and EIF2 signaling is a target of the ER-stress UPR pathway, we sought to ascertain whether this finding was specifically associated with tau pathology. To investigate this, we performed immunohistochemistry on eight brain regions either selectively vulnerable in PSP (subthalamic nucleus and adjacent thalamus, peri-Rolandic cortex, putamen, globus pallidus, caudate, dentate nucleus of cerebellum) or protected (occipital cortex) on ten PSP cases and six matched-controls using an antibody for phosphorylated eIF2α (peIF2α), the activated form of this protein [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 101" title="Roemer SF, Grinberg LT, Crary JF, Seeley WW, McKee AC, Kovacs GG et al (2022) Rainwater charitable foundation criteria for the neuropathologic diagnosis of progressive supranuclear palsy. Acta Neuropathol 144:603–614. 
 https://doi.org/10.1007/s00401-022-02479-4
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR101" id="ref-link-section-d390719442e2917">101</a>] (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/article/10.1007/s00401-024-02823-w#Tab3">3</a>, Supplementary Data <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/article/10.1007/s00401-024-02823-w#MOESM1">1</a>). Phospho-eIF2α staining highlighted numerous cytoplasmic granules with vacuolar features in positive cells (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02823-w#Fig5">5</a>a). To quantify peIF2α signal, we counted the number of PSP cases and controls with positive cells in each region (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02823-w#Fig5">5</a>b). No peIF2α positive (peIF2α<sup>+</sup>) cells were detected in any brain region in the controls. Phospho-eIF2α<sup>+</sup> cells were detected in the subthalamic nucleus, thalamus, and putamen in nine of the ten PSP cases, and all vulnerable brain regions had significantly more peIF2α<sup>+</sup> PSP cases than controls (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02823-w#Fig5">5</a>b). To further investigate peIF2α burden in PSP, we counted the number of peIF2α<sup>+</sup> cells in the sampled vulnerable and protected PSP brain regions and scored semi-quantitatively from absent ( – ) to > 2 positive cells per mm<sup>2</sup> (+ + +) (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02823-w#Fig5">5</a>c). The putamen, thalamus, subthalamic nucleus, and caudate had the highest number of peIF2α<sup>+</sup> cells while no peIF2α<sup>+</sup> cells were detected in the occipital cortex. These data show regional peIF2α burden is consistent with patterns of tau burden across vulnerable brain regions in PSP.</p><div class="c-article-table" data-test="inline-table" data-container-section="table" id="table-3"><figure><figcaption class="c-article-table__figcaption"><b id="Tab3" data-test="table-caption">Table 3 IHC validation patient table</b></figcaption><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="table-link" data-track="click" data-track-action="view table" data-track-label="button" rel="nofollow" href="/article/10.1007/s00401-024-02823-w/tables/3" aria-label="Full size table 3"><span>Full size table</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-5" data-title="Fig. 5"><figure><figcaption><b id="Fig5" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 5</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/article/10.1007/s00401-024-02823-w/figures/5" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs00401-024-02823-w/MediaObjects/401_2024_2823_Fig5_HTML.png?as=webp"><img aria-describedby="Fig5" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs00401-024-02823-w/MediaObjects/401_2024_2823_Fig5_HTML.png" alt="figure 5" loading="lazy" width="685" height="698"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-5-desc"><p>Elevated eIF2α and correlation with tau pathology in PSP vulnerable brain regions. <b>a</b> Representative images of peIF2α immunohistochemistry across brain regions showing peIF2α + granules in all PSP regions except the visual cortex and no positive granules in controls, scale bar 50–10 µm. <i>STN</i> subthalamic nucleus; <i>MC</i> motor cortex; <i>GP</i> Globus Pallidus; <i>CB</i> cerebellum; <i>VC</i> visual cortex <b>b</b> Quantification of (<b>a</b>) showing significant differences in the number of PSP and controls positive and negative for peIF2α + cells in all brain regions except the visual cortex. Comparisons were performed using Fisher’s exact test. <b>c</b> Summary of scaled peIF2α burden across brain regions in PSP cases. Scaling was calculated using # peIF2α + cells/mm<sup>2</sup>; -, 0; + , < 1; + + , < 2; + + + , > 2.<b> d</b>–<b>e</b> Correlations between peIF2α and p-tau pathology in the STN (<b>d</b>) and thalamus (<b>e</b>), <i>NT</i> neuropil threads; <i>NFT</i> neurofibrillary tangles, <i>GFT</i> glial fibrillary tangles. <b>f</b> Multiplex immunofluorescence showing colocalization of peIF2α (red) with p-tau (AT8, orange) positive neurons (top) and ALDH1L1 (green)-labeled astrocytes (bottom) in PSP, scale bar 25 µm</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/article/10.1007/s00401-024-02823-w/figures/5" data-track-dest="link:Figure5 Full size image" aria-label="Full size image figure 5" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>To further investigate the relationship between increased EIF2 activation and tau accumulation, we explored whether tau burden correlated with the number of peIF2α<sup>+</sup> cells in the subthalamic nucleus and thalamus. Phosphorylated tau burden was measured on whole slide images of AT8-stained sections by semi-quantitative scoring ( – absent, + mild, + + moderate, + + + severe) for neuropil threads (NT), neurofibrillary tangles (NFT), and glial fibrillary tangles (GFT), and by positive pixels. The number of peIF2α<sup>+</sup> cells significantly positively correlated with all measures of tau burden in the subthalamic nucleus and thalamus (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02823-w#Fig5">5</a>d, e, Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/article/10.1007/s00401-024-02823-w#Tab4">4</a>).</p><div class="c-article-table" data-test="inline-table" data-container-section="table" id="table-4"><figure><figcaption class="c-article-table__figcaption"><b id="Tab4" data-test="table-caption">Table 4 Summary of pEIF2α and AT8 correlation</b></figcaption><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="table-link" data-track="click" data-track-action="view table" data-track-label="button" rel="nofollow" href="/article/10.1007/s00401-024-02823-w/tables/4" aria-label="Full size table 4"><span>Full size table</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>Finally, we performed multiplexed immunofluorescence to localize peIF2α positivity to different cell types by labeling nuclei (DAPI), astrocytes (ALDH1L1), peIF2α, and phospho-tau inclusions (AT8). We observed peIF2α granules in both p-tau positive neurons and p-tau positive astrocytes (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02823-w#Fig5">5</a>f). These results show EIF2 activation in PSP neurons and astrocytes with tau inclusions and provide histological validation to support the increased transcriptomic EIF2 activation observed in multiple cell types that are vulnerable to tau accumulation in PSP. Together these data show a quantitative association of peIF2α with tau burden in PSP specifically in vulnerable cell populations and brain regions.</p><h3 class="c-article__sub-heading" id="Sec19">Differential gene expression and dysregulated functions in cell types not vulnerable in PSP</h3><p>We also observed gene expression differences in other cell types not affected by tau accumulation in PSP (Supplementary Figs. 4–5, Supplementary Data <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/article/10.1007/s00401-024-02823-w#MOESM3">3</a>). PSP microglia overexpressed several ribosomal and heat shock genes related to topologically incorrect protein degradation, ER stress and PERK regulation, and were associated with activation of EIF2 signaling and other stress response pathways (Supplementary Fig. 5b). PSP endothelial cells differentially expressed several genes specific to endothelial cell function, homeostasis and secreted proteins including connective tissue growth factor (<i>CTGF)</i>, and metallothionein (<i>MT1X)</i> [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 17" title="Brigstock DR (2002) Regulation of angiogenesis and endothelial cell function by connective tissue growth factor (CTGF) and cysteine-rich 61 (CYR61). Angiogenesis 5:153–165. 
 https://doi.org/10.1023/a:1023823803510
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR17" id="ref-link-section-d390719442e3572">17</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 41" title="Greene C, Hanley N, Campbell M (2019) Claudin-5: gatekeeper of neurological function. Fluids Barriers CNS 16:3. 
 https://doi.org/10.1186/s12987-019-0123-z
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR41" id="ref-link-section-d390719442e3575">41</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 106" title="Schulkens IA, Castricum KC, Weijers EM, Koolwijk P, Griffioen AW, Thijssen VL (2014) Expression, regulation and function of human metallothioneins in endothelial cells. J Vasc Res 51:231–238. 
 https://doi.org/10.1159/000365550
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR106" id="ref-link-section-d390719442e3579">106</a>]. PSP ChP cells downregulated claudin-5 (<i>CLDN5</i>), the most enriched tight junction protein at the blood brain barrier [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 41" title="Greene C, Hanley N, Campbell M (2019) Claudin-5: gatekeeper of neurological function. Fluids Barriers CNS 16:3. 
 https://doi.org/10.1186/s12987-019-0123-z
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR41" id="ref-link-section-d390719442e3585">41</a>]. These data suggests that PSP-related dysregulated functions, such as EIF2 signaling and ER stress, and blood–brain barrier breakdown, are dysregulated in cell types not affected by p-tau accumulation and warrants further investigation into these cell types as reactive or promoting disease states in degenerating cell types in PSP.</p></div></div></section><section data-title="Discussion"><div class="c-article-section" id="Sec20-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec20">Discussion</h2><div class="c-article-section__content" id="Sec20-content"><p>These are the first data to demonstrate transcriptomic changes using single nucleus RNA-sequencing (snRNA-seq) in the brainstem of patients with PSP, a region which is selectively vulnerable in this disease. We show distinct cell populations known to be susceptible to abnormal tau accumulation (i.e., neurons, astrocytes, and oligodendrocytes) that exhibit differential gene expression patterns and enrichment of cell death and injury pathways, including neuronal populations that are reduced in PSP. Many genes related to protein translation and endoplasmic reticulum (ER) stress were differentially expressed, and EIF2 signaling and other related stress pathways were dysregulated across vulnerable cell types. These findings were replicated in two independent publicly available datasets. These findings were also validated histopathologically, with co-localization of activated phospho-eIF2α (peIF2α) in p-tau positive neurons and astrocytes. Further, eIF2α activation positively correlated with tau pathology burden. Brain regions that are most vulnerable in PSP displayed the highest peIF2α burden, whereas no signal was observed in protected regions.</p><p>EIF2 signaling is activated by phosphorylation under stress conditions in a signaling program known as the integrated stress response (ISR) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 22" title="Costa-Mattioli M, Walter P (2020) The integrated stress response: from mechanism to disease. Science. 
 https://doi.org/10.1126/science.aat5314
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR22" id="ref-link-section-d390719442e3600">22</a>]. The ISR is activated by multiple cellular stressors, including heme depletion, ER stress, viral infection, amino acid starvation, and heat shock [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 86" title="Pakos-Zebrucka K, Koryga I, Mnich K, Ljujic M, Samali A, Gorman AM (2016) The integrated stress response. EMBO Rep 17:1374–1395. 
 https://doi.org/10.15252/embr.201642195
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR86" id="ref-link-section-d390719442e3603">86</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 119" title="Taniuchi S, Miyake M, Tsugawa K, Oyadomari M, Oyadomari S (2016) Integrated stress response of vertebrates is regulated by four eIF2alpha kinases. Sci Rep 6:32886. 
 https://doi.org/10.1038/srep32886
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR119" id="ref-link-section-d390719442e3606">119</a>]. ER stress is mediated by the unfolded protein response (UPR), which is composed of three branches initiated by protein kinase RNA-like ER kinase (PERK), inositol-requiring protein 1α (IRE1α), and activating transcription factor 6 (ATF6) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 51" title="Hetz C (2012) The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol 13:89–102. 
 https://doi.org/10.1038/nrm3270
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR51" id="ref-link-section-d390719442e3609">51</a>]. GWAS studies identified <i>EIF2AK3</i>, which codes for PERK, as a risk allele for PSP, thereby implicating the PERK/EIF2 pathway, the ISR, and the UPR in the pathogenesis of PSP [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Chen JA, Chen Z, Won H, Huang AY, Lowe JK, Wojta K et al (2018) Joint genome-wide association study of progressive supranuclear palsy identifies novel susceptibility loci and genetic correlation to neurodegenerative diseases. Mol Neurodegener 13:41. 
 https://doi.org/10.1186/s13024-018-0270-8
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR20" id="ref-link-section-d390719442e3616">20</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 53" title="Hoglinger GU, Melhem NM, Dickson DW, Sleiman PM, Wang LS, Klei L et al (2011) Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet 43:699–705. 
 https://doi.org/10.1038/ng.859
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR53" id="ref-link-section-d390719442e3619">53</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 104" title="Sanchez-Contreras MY, Kouri N, Cook CN, Serie DJ, Heckman MG, Finch NA et al (2018) Replication of progressive supranuclear palsy genome-wide association study identifies SLCO1A2 and DUSP10 as new susceptibility loci. Mol Neurodegener 13:37. 
 https://doi.org/10.1186/s13024-018-0267-3
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR104" id="ref-link-section-d390719442e3622">104</a>].</p><p>In this study, increased EIF2 signaling in PSP neurons was driven by altered expression of ribosomal, chaperone, and heat shock genes, as well as other genes related to protein quality control, the unfolded protein response and ER stress. Increased EIF2 signaling in PSP astrocytes and oligodendrocytes was driven by these gene sets and additionally by differential expression of genes specific to the individual UPR branches including PERK-regulated genes. UPR overactivation under chronic stress or abnormal eIF2α phosphorylation can trigger apoptosis [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 51" title="Hetz C (2012) The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol 13:89–102. 
 https://doi.org/10.1038/nrm3270
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR51" id="ref-link-section-d390719442e3628">51</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 112" title="Srivastava SP, Kumar KU, Kaufman RJ (1998) Phosphorylation of eukaryotic translation initiation factor 2 mediates apoptosis in response to activation of the double-stranded RNA-dependent protein kinase. J Biol Chem 273:2416–2423. 
 https://doi.org/10.1074/jbc.273.4.2416
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR112" id="ref-link-section-d390719442e3631">112</a>]. In our dataset, genes and pathways related to apoptosis regulation and autophagy signaling were also dysregulated in astrocytes, oligodendrocytes, and in the neuronal clusters with reduced enrichment in PSP. Although the relationship between the UPR and autophagy has been well studied in neurons, its role in regulating cell autonomous and non-cell autonomous functions in other cell types has not been well studied [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Ajoolabady A, Lindholm D, Ren J, Pratico D (2022) ER stress and UPR in Alzheimer’s disease: mechanisms, pathogenesis, treatments. Cell Death Dis 13:706. 
 https://doi.org/10.1038/s41419-022-05153-5
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR3" id="ref-link-section-d390719442e3634">3</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 64" title="Kwon J, Kim J, Kim KI (2023) Crosstalk between endoplasmic reticulum stress response and autophagy in human diseases. Anim Cells Syst (Seoul) 27:29–37. 
 https://doi.org/10.1080/19768354.2023.2181217
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR64" id="ref-link-section-d390719442e3637">64</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 97" title="Ren H, Zhai W, Lu X, Wang G (2021) The cross-links of endoplasmic reticulum stress, autophagy, and neurodegeneration in Parkinson’s disease. Front Aging Neurosci 13:691881. 
 https://doi.org/10.3389/fnagi.2021.691881
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR97" id="ref-link-section-d390719442e3640">97</a>]. Previous single-cell RNA-seq (scRNA-seq) studies in tau burdened neurodegenerative postmortem brain tissue have identified similar stress response pathways in vulnerable cell types. In an AD scRNA-seq study, AD astrocyte and neuron subclusters were enriched for genes relating to responses to incorrectly folded proteins [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 42" title="Grubman A, Chew G, Ouyang JF, Sun G, Choo XY, McLean C et al (2019) A single-cell atlas of entorhinal cortex from individuals with Alzheimer’s disease reveals cell-type-specific gene expression regulation. Nat Neurosci 22:2087–2097. 
 https://doi.org/10.1038/s41593-019-0539-4
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR42" id="ref-link-section-d390719442e3644">42</a>]. A single-soma RNA-seq study found that the ISR transcription factor ATF4, which is translated by eIF2α phosphorylation, and other heat shock proteins were highly upregulated in NFT-bearing neurons [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 85" title="Otero-Garcia M, Mahajani SU, Wakhloo D, Tang W, Xue YQ, Morabito S et al (2022) Molecular signatures underlying neurofibrillary tangle susceptibility in Alzheimer’s disease. Neuron 110(2929–2948):e2928. 
 https://doi.org/10.1016/j.neuron.2022.06.021
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR85" id="ref-link-section-d390719442e3647">85</a>]. In a PD snRNA-seq study, PD microglia and astrocytes upregulated chaperone and heat shock genes coupled with UPR dysregulation [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 110" title="Smajic S, Prada-Medina CA, Landoulsi Z, Ghelfi J, Delcambre S, Dietrich C et al (2022) Single-cell sequencing of human midbrain reveals glial activation and a Parkinson-specific neuronal state. Brain 145:964–978. 
 https://doi.org/10.1093/brain/awab446
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR110" id="ref-link-section-d390719442e3650">110</a>]. It is unclear if UPR-dysregulation is a common stress mechanism that affects multiple cell types in the brain during toxic misfolded protein aggregate-mediated neurodegeneration, or if the GWAS risk-associated <i>EIF2AK3</i> underlies a unique pathogenic mechanism specific to PSP.</p><p>UPR activation has been observed histologically in multiple neurodegenerative diseases; however, its role in disease pathogenesis is unclear. Here we show that EIF2 activation (peIF2α) in neurons and astrocytes positively correlates with p-tau burden and distribution patterns in brain regions vulnerable in PSP. Activated peIF2α co-localized with neurofibrillary tangles, and tau-positive astrocytes. Our study is the first to our knowledge to demonstrate histological evidence of UPR activation in astrocytes in postmortem tauopathy brain tissue. Other histological studies have also shown neuronal UPR activation occurs in PSP, AD, C9orf72-FTD, and PD post-mortem brain tissue [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 38" title="Gami-Patel P, van Dijken I, Meeter LH, Melhem S, Morrema THJ, Scheper W et al (2021) Unfolded protein response activation in C9orf72 frontotemporal dementia is associated with dipeptide pathology and granulovacuolar degeneration in granule cells. Brain Pathol 31:163–173. 
 https://doi.org/10.1111/bpa.12894
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR38" id="ref-link-section-d390719442e3659">38</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 54" title="Hoozemans JJ, van Haastert ES, Nijholt DA, Rozemuller AJ, Eikelenboom P, Scheper W (2009) The unfolded protein response is activated in pretangle neurons in Alzheimer’s disease hippocampus. Am J Pathol 174:1241–1251. 
 https://doi.org/10.2353/ajpath.2009.080814
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR54" id="ref-link-section-d390719442e3662">54</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 55" title="Hoozemans JJ, van Haastert ES, Nijholt DA, Rozemuller AJ, Scheper W (2012) Activation of the unfolded protein response is an early event in Alzheimer’s and Parkinson’s disease. Neurodegener Dis 10:212–215. 
 https://doi.org/10.1159/000334536
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR55" id="ref-link-section-d390719442e3665">55</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 84" title="Nijholt DA, van Haastert ES, Rozemuller AJ, Scheper W, Hoozemans JJ (2012) The unfolded protein response is associated with early tau pathology in the hippocampus of tauopathies. J Pathol 226:693–702. 
 https://doi.org/10.1002/path.3969
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR84" id="ref-link-section-d390719442e3668">84</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 115" title="Stutzbach LD, Xie SX, Naj AC, Albin R, Gilman S, Group PSPGS et al (2013) The unfolded protein response is activated in disease-affected brain regions in progressive supranuclear palsy and Alzheimer’s disease. Acta Neuropathol Commun 1:31. 
 https://doi.org/10.1186/2051-5960-1-31
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR115" id="ref-link-section-d390719442e3671">115</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 121" title="Unterberger U, Hoftberger R, Gelpi E, Flicker H, Budka H, Voigtlander T (2006) Endoplasmic reticulum stress features are prominent in Alzheimer disease but not in prion diseases in vivo. J Neuropathol Exp Neurol 65:348–357. 
 https://doi.org/10.1097/01.jnen.0000218445.30535.6f
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR121" id="ref-link-section-d390719442e3675">121</a>]. Neuronal PERK activation by phosphorylation (pPERK) is seen in PSP brain regions highly affected by tau and has been shown to co-localize with neuronal tau histologically [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 115" title="Stutzbach LD, Xie SX, Naj AC, Albin R, Gilman S, Group PSPGS et al (2013) The unfolded protein response is activated in disease-affected brain regions in progressive supranuclear palsy and Alzheimer’s disease. Acta Neuropathol Commun 1:31. 
 https://doi.org/10.1186/2051-5960-1-31
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR115" id="ref-link-section-d390719442e3678">115</a>]. However, other studies have found no correlation between tau accumulation and UPR activation in post-mortem AD and PSP brain tissue [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 90" title="Pitera AP, Hartnell IJ, Scullard L, Williamson KL, Boche D, O’Connor V et al (2021) Molecular investigation of the unfolded protein response in select human tauopathies. J Alzheimers Dis Rep 5:855–869. 
 https://doi.org/10.3233/ADR-210050
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR90" id="ref-link-section-d390719442e3681">90</a>]. These previous studies have focused on total p-tau levels and neuronal p-tau; therefore, it remains unclear if p-tau accumulation in glial cells induces PERK activation in human brain tissue. Future biochemical studies of peIF2α protein levels in human brain are needed to further characterize changes in protein expression.</p><p>In vivo studies have thus far not shown a consistent relationship between UPR activity and tau aggregation. Several studies have demonstrated UPR activation triggers tau accumulation and contributes to cell vulnerability and neurodegeneration. Increased UPR activation and vulnerability to ER stressors is seen in <i>MAPT</i>-mutation carrying iPSC-derived neurons with abnormal tau accumulation [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 28" title="Ehrlich M, Hallmann AL, Reinhardt P, Arauzo-Bravo MJ, Korr S, Ropke A et al (2015) Distinct neurodegenerative changes in an induced pluripotent stem cell model of frontotemporal dementia linked to mutant TAU protein. Stem Cell Reports 5:83–96. 
 https://doi.org/10.1016/j.stemcr.2015.06.001
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR28" id="ref-link-section-d390719442e3691">28</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 109" title="Silva MC, Cheng C, Mair W, Almeida S, Fong H, Biswas MHU et al (2016) Human iPSC-derived neuronal model of Tau-A152T frontotemporal dementia reveals Tau-mediated mechanisms of neuronal vulnerability. Stem Cell Reports 7:325–340. 
 https://doi.org/10.1016/j.stemcr.2016.08.001
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR109" id="ref-link-section-d390719442e3694">109</a>]. Tau accumulation was shown to activate the UPR in human AD brains, tau<sup>P301L</sup> mice and iHEK-Tau cells [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Abisambra JF, Jinwal UK, Blair LJ, O’Leary JC 3rd, Li Q, Brady S et al (2013) Tau accumulation activates the unfolded protein response by impairing endoplasmic reticulum-associated degradation. J Neurosci 33:9498–9507. 
 https://doi.org/10.1523/JNEUROSCI.5397-12.2013
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR1" id="ref-link-section-d390719442e3699">1</a>]. Activation of PERK-peIF2α-mediated UPR signaling in astrocytes in vivo and of mice infected with prion protein has been shown to drive non-cell autonomous neurodegeneration [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 111" title="Smith HL, Freeman OJ, Butcher AJ, Holmqvist S, Humoud I, Schatzl T et al (2020) Astrocyte unfolded protein response induces a specific reactivity state that causes non-cell-autonomous neuronal degeneration. Neuron 105(855–866):e855. 
 https://doi.org/10.1016/j.neuron.2019.12.014
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR111" id="ref-link-section-d390719442e3703">111</a>]. ISR activation in astrocytes was also shown to be an early, cell non-autonomous response to neuronal tau aggregation in a human neuron-astrocyte co-culture model [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 11" title="Batenburg KL, Kasri NN, Heine VM, Scheper W (2023) Intraneuronal tau aggregation induces the integrated stress response in astrocytes. J Mol Cell Biol. 
 https://doi.org/10.1093/jmcb/mjac071
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR11" id="ref-link-section-d390719442e3706">11</a>]. Additionally, the UPR was identified as an enriched pathway in a 3D neuron-astrocyte tauopathy assembloid model [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 99" title="Rickner HD, Jiang L, Hong R, O’Neill NK, Mojica CA, Snyder BJ et al (2022) Single cell transcriptomic profiling of a neuron-astrocyte assembloid tauopathy model. Nat Commun 13:6275. 
 https://doi.org/10.1038/s41467-022-34005-1
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR99" id="ref-link-section-d390719442e3709">99</a>]. However, other studies found UPR activation to be neuroprotective and reduce p-tau burden. PERK activation reduced tau phosphorylation and increased cell survival in a 4R-tau overexpression neuronal model [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 19" title="Bruch J, Xu H, Rosler TW, De Andrade A, Kuhn PH, Lichtenthaler SF et al (2017) PERK activation mitigates tau pathology in vitro and in vivo. EMBO Mol Med 9:371–384. 
 https://doi.org/10.15252/emmm.201606664
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR19" id="ref-link-section-d390719442e3712">19</a>]. PERK activation also prevented tau aggregation in vivo and reduced PERK signaling correlated with increased tau neuropathology in postmortem AD brains [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 87" title="Park G, Xu K, Chea L, Kim K, Safarta L, Song KH et al (2023) Neurodegeneration risk factor, EIF2AK3 (PERK), influences tau protein aggregation. J Biol Chem 299:102821. 
 https://doi.org/10.1016/j.jbc.2022.102821
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR87" id="ref-link-section-d390719442e3715">87</a>]. Still other groups have found no correlation between tau accumulation and UPR activation in tau<sup>P301L</sup> mice or tau<sup>P301L</sup> primary neurons [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 89" title="Pitera AP, Asuni AA, O’Connor V, Deinhardt K (2019) Pathogenic tau does not drive activation of the unfolded protein response. J Biol Chem 294:9679–9688. 
 https://doi.org/10.1074/jbc.RA119.008263
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR89" id="ref-link-section-d390719442e3723">89</a>]. Many of these studies utilized mouse models or immortal cell line tau aggregation models to investigate UPR activation, which may not accurately recapitulate the cellular and molecular complexity of neurodegeneration in the human brain. Further examination of the mechanistic relationship between UPR activation and tau accumulation are needed in patient-derived induced pluripotent stem cell (iPSC) models that critically retain diseased patient genetic backgrounds.</p><p>Neuronal loss is a shared pathological feature across neurodegenerative disorders, including PSP [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 26" title="Dickson DW, Rademakers R, Hutton ML (2007) Progressive supranuclear palsy: pathology and genetics. Brain Pathol 17:74–82. 
 https://doi.org/10.1111/j.1750-3639.2007.00054.x
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR26" id="ref-link-section-d390719442e3729">26</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Forrest SL, Kril JJ, Halliday GM (2019) Cellular and regional vulnerability in frontotemporal tauopathies. Acta Neuropathol 138:705–727. 
 https://doi.org/10.1007/s00401-019-02035-7
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR33" id="ref-link-section-d390719442e3732">33</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 126" title="Wilson DM 3rd, Cookson MR, Van Den Bosch L, Zetterberg H, Holtzman DM, Dewachter I (2023) Hallmarks of neurodegenerative diseases. Cell 186:693–714. 
 https://doi.org/10.1016/j.cell.2022.12.032
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR126" id="ref-link-section-d390719442e3735">126</a>]. We identified four neuronal clusters with reduced enrichment in PSP which are marked by apoptotic genes including <i>CELF2</i>. <i>CELF2</i> overexpression promotes apoptosis via regulating the endoplasmic reticulum associated degradation (ERAD) pathway and has been linked to AD [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 66" title="Lai S, Wang Y, Li T, Dong Y, Lin Y, Wang L et al (2022) N6-methyladenosine-mediated CELF2 regulates CD44 alternative splicing affecting tumorigenesis via ERAD pathway in pancreatic cancer. Cell Biosci 12:125. 
 https://doi.org/10.1186/s13578-022-00844-0
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR66" id="ref-link-section-d390719442e3745">66</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 130" title="Yanaizu M, Washizu C, Nukina N, Satoh JI, Kino Y (2020) CELF2 regulates the species-specific alternative splicing of TREM2. Sci Rep 10:17995. 
 https://doi.org/10.1038/s41598-020-75057-x
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR130" id="ref-link-section-d390719442e3748">130</a>]. Neuronal cells from PSP patients overexpressed genes related to neuronal injury and downregulated several genes related to apoptosis regulation such as <i>JUND</i>, <i>IFI6,</i> and <i>MTRNR2L12. JUND</i> is proposed to protect cells from senescence and apoptosis, and <i>IFI6</i> is an interferon-stimulated gene that has been shown to inhibit apoptosis in vascular endothelial cells [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 91" title="Qi Y, Li Y, Zhang Y, Zhang L, Wang Z, Zhang X et al (2015) IFI6 inhibits apoptosis via mitochondrial-dependent pathway in dengue virus 2 infected vascular endothelial cells. PLoS ONE 10:e0132743. 
 https://doi.org/10.1371/journal.pone.0132743
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR91" id="ref-link-section-d390719442e3764">91</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 124" title="Weitzman JB, Fiette L, Matsuo K, Yaniv M (2000) JunD protects cells from p53-dependent senescence and apoptosis. Mol Cell 6:1109–1119. 
 https://doi.org/10.1016/s1097-2765(00)00109-x
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR124" id="ref-link-section-d390719442e3767">124</a>]. <i>MTRNR2L12</i> codes for an isoform of humanin, a secreted peptide with neuroprotective effects by modulation of oxidative stress and apoptosis [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 133" title="Zarate SC, Traetta ME, Codagnone MG, Seilicovich A, Reines AG (2019) Humanin, a mitochondrial-derived peptide released by astrocytes, prevents synapse loss in hippocampal neurons. Front Aging Neurosci 11:123. 
 https://doi.org/10.3389/fnagi.2019.00123
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR133" id="ref-link-section-d390719442e3773">133</a>]. Humanin is protective against neuronal cell death in familial AD and <i>MTRNR2L12</i> is a potential blood biomarker for early AD-like dementia in Down syndrome [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 14" title="Bik-Multanowski M, Pietrzyk JJ, Midro A (2015) MTRNR2L12: A candidate blood marker of early Alzheimer’s disease-like dementia in adults with down syndrome. J Alzheimers Dis 46:145–150. 
 https://doi.org/10.3233/JAD-143030
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR14" id="ref-link-section-d390719442e3779">14</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 48" title="Hashimoto Y, Niikura T, Tajima H, Yasukawa T, Sudo H, Ito Y et al (2001) A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer’s disease genes and Abeta. Proc Natl Acad Sci U S A 98:6336–6341. 
 https://doi.org/10.1073/pnas.101133498
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR48" id="ref-link-section-d390719442e3783">48</a>]. Differential gene expression and pathway analysis indicated several critical neuronal functions including calcium-mediated signaling are also dysregulated in these clusters. Disruption of calcium homeostasis and activation of calmodulin-dependent CAMKII has been shown to impair synaptic morphology and trigger neuronal apoptosis in AD [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 13" title="Bezprozvanny I, Mattson MP (2008) Neuronal calcium mishandling and the pathogenesis of Alzheimer’s disease. Trends Neurosci 31:454–463. 
 https://doi.org/10.1016/j.tins.2008.06.005
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR13" id="ref-link-section-d390719442e3786">13</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 65" title="LaFerla FM (2002) Calcium dyshomeostasis and intracellular signalling in Alzheimer’s disease. Nat Rev Neurosci 3:862–872. 
 https://doi.org/10.1038/nrn960
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR65" id="ref-link-section-d390719442e3789">65</a>]. CAMKIIA also associates with and phosphorylates tau at multiple sites to induce a conformational change to generate paired helical fragment conformation [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Baudier J, Cole RD (1987) Phosphorylation of tau proteins to a state like that in Alzheimer’s brain is catalyzed by a calcium/calmodulin-dependent kinase and modulated by phospholipids. J Biol Chem 262:17577–17583" href="/article/10.1007/s00401-024-02823-w#ref-CR12" id="ref-link-section-d390719442e3792">12</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 45" title="Hagestedt T, Lichtenberg B, Wille H, Mandelkow EM, Mandelkow E (1989) Tau protein becomes long and stiff upon phosphorylation: correlation between paracrystalline structure and degree of phosphorylation. J Cell Biol 109:1643–1651. 
 https://doi.org/10.1083/jcb.109.4.1643
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR45" id="ref-link-section-d390719442e3795">45</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 113" title="Steiner B, Mandelkow EM, Biernat J, Gustke N, Meyer HE, Schmidt B et al (1990) Phosphorylation of microtubule-associated protein tau: identification of the site for Ca2(+)-calmodulin dependent kinase and relationship with tau phosphorylation in Alzheimer tangles. EMBO J 9:3539–3544. 
 https://doi.org/10.1002/j.1460-2075.1990.tb07563.x
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR113" id="ref-link-section-d390719442e3798">113</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 128" title="Xiao J, Perry G, Troncoso J, Monteiro MJ (1996) alpha-calcium-calmodulin-dependent kinase II is associated with paired helical filaments of Alzheimer’s disease. J Neuropathol Exp Neurol 55:954–963. 
 https://doi.org/10.1097/00005072-199609000-00002
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR128" id="ref-link-section-d390719442e3802">128</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 131" title="Yoshimura Y, Ichinose T, Yamauchi T (2003) Phosphorylation of tau protein to sites found in Alzheimer’s disease brain is catalyzed by Ca2+/calmodulin-dependent protein kinase II as demonstrated tandem mass spectrometry. Neurosci Lett 353:185–188. 
 https://doi.org/10.1016/j.neulet.2003.09.037
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR131" id="ref-link-section-d390719442e3805">131</a>]. Neuron clusters also upregulated calcium ion binding and calmodulin-mediated signaling regulator <i>PCP4.</i> Interestingly, PCP4 levels are decreased in the brains of patients with AD and HD, but not in PD [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 122" title="Utal AK, Stopka AL, Roy M, Coleman PD (1998) PEP-19 immunohistochemistry defines the basal ganglia and associated structures in the adult human brain, and is dramatically reduced in Huntington’s disease. Neuroscience 86:1055–1063. 
 https://doi.org/10.1016/s0306-4522(98)00130-4
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR122" id="ref-link-section-d390719442e3811">122</a>]. Decreased expression of apoptotic regulating genes in the PSP-reduced neuronal clusters may indicate neuronal populations vulnerable to tau accumulation or undergoing neurodegeneration.</p><p>We also identified two neuronal clusters that were not enriched in controls. These neuronal populations are marked by <i>PP3CA</i>, <i>ARPP19</i> and <i>ARPP21</i>, genes related to protein phosphorylation, particularly tau phosphorylation. <i>PPP3CA</i> (also known as calcineurin) is the only phosphatase directly modulated by calcium to control synaptic transmission and other neuronal processes and is one of the major phosphatases that directly regulates tau phosphorylation and dephosphorylates p-tau in the brain [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 21" title="Colbran RJ (2004) Protein phosphatases and calcium/calmodulin-dependent protein kinase II-dependent synaptic plasticity. J Neurosci 24:8404–8409. 
 https://doi.org/10.1523/JNEUROSCI.3602-04.2004
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR21" id="ref-link-section-d390719442e3829">21</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 40" title="Gong CX, Shaikh S, Wang JZ, Zaidi T, Grundke-Iqbal I, Iqbal K (1995) Phosphatase activity toward abnormally phosphorylated tau: decrease in Alzheimer disease brain. J Neurochem 65:732–738. 
 https://doi.org/10.1046/j.1471-4159.1995.65020732.x
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR40" id="ref-link-section-d390719442e3833">40</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 92" title="Qian W, Yin X, Hu W, Shi J, Gu J, Grundke-Iqbal I et al (2011) Activation of protein phosphatase 2B and hyperphosphorylation of Tau in Alzheimer’s disease. J Alzheimers Dis 23:617–627. 
 https://doi.org/10.3233/JAD-2010-100987
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR92" id="ref-link-section-d390719442e3836">92</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 94" title="Rahman A, Grundke-Iqbal I, Iqbal K (2006) PP2B isolated from human brain preferentially dephosphorylates Ser-262 and Ser-396 of the Alzheimer disease abnormally hyperphosphorylated tau. J Neural Transm (Vienna) 113:219–230. 
 https://doi.org/10.1007/s00702-005-0313-5
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR94" id="ref-link-section-d390719442e3839">94</a>]. <i>PPP3CA</i> expression and activity is reduced in the brains of AD patients, and reduced <i>PPP3CA</i> activity leads to tau hyperphosphorylation in other tauopathies including chronic traumatic encephalopathy (CTE) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 40" title="Gong CX, Shaikh S, Wang JZ, Zaidi T, Grundke-Iqbal I, Iqbal K (1995) Phosphatase activity toward abnormally phosphorylated tau: decrease in Alzheimer disease brain. J Neurochem 65:732–738. 
 https://doi.org/10.1046/j.1471-4159.1995.65020732.x
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR40" id="ref-link-section-d390719442e3848">40</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 107" title="Seo JS, Lee S, Shin JY, Hwang YJ, Cho H, Yoo SK et al (2017) Transcriptome analyses of chronic traumatic encephalopathy show alterations in protein phosphatase expression associated with tauopathy. Exp Mol Med 49:e333. 
 https://doi.org/10.1038/emm.2017.56
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR107" id="ref-link-section-d390719442e3852">107</a>]. <i>ARPP19</i> and <i>ARPP21</i> are substrates for calcium dependent cAMP-dependent protein kinase (PKA), and expression of <i>ARPP19</i> is reduced in AD brains [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 58" title="Kim SH, Nairn AC, Cairns N, Lubec G (2001) Decreased levels of ARPP-19 and PKA in brains of down syndrome and Alzheimer’s disease. J Neural Transm Suppl. 
 https://doi.org/10.1007/978-3-7091-6262-0_21
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR58" id="ref-link-section-d390719442e3864">58</a>]. Reduced activity of the genes marking non-depleted clusters are implicated in neurodegeneration, therefore the overexpression of these genes may indicate spared or protected neuronal populations. Of note, these cell clusters are mainly comprised of cells from samples with the largest cell counts.</p><p>Our data provide further evidence to support additional genes and mechanisms previously implicated in PSP, AD, and other neurodegenerative diseases, including iron accumulation and oxygen homeostasis, blood brain barrier breakdown, and several AD-associated genes. PSP neurons and astrocytes overexpressed genes involved in heavy metal and iron accumulation and oxygen homeostasis, and ferroptosis signaling was overactivated in PSP astrocytes and oligodendrocytes. Multiple studies have shown ferritin protein defects, abnormal iron accumulation, and oxygen homeostasis in the brain is associated with neurodegenerative diseases, including PSP, PD, and AD [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 23" title="Dexter DT, Carayon A, Javoy-Agid F, Agid Y, Wells FR, Daniel SE et al (1991) Alterations in the levels of iron, ferritin and other trace metals in Parkinson’s disease and other neurodegenerative diseases affecting the basal ganglia. Brain 114(Pt 4):1953–1975. 
 https://doi.org/10.1093/brain/114.4.1953
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR23" id="ref-link-section-d390719442e3870">23</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Ferrer I, Gomez A, Carmona M, Huesa G, Porta S, Riera-Codina M et al (2011) Neuronal hemoglobin is reduced in Alzheimer’s disease, argyrophilic grain disease, Parkinson’s disease, and dementia with Lewy bodies. J Alzheimers Dis 23:537–550. 
 https://doi.org/10.3233/JAD-2010-101485
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR30" id="ref-link-section-d390719442e3873">30</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 32" title="Foroutan P, Murray ME, Fujioka S, Schweitzer KJ, Dickson DW, Wszolek ZK et al (2013) Progressive supranuclear palsy: high-field-strength MR microscopy in the human substantia nigra and globus pallidus. Radiology 266:280–288. 
 https://doi.org/10.1148/radiol.12102273
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR32" id="ref-link-section-d390719442e3876">32</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 60" title="Koh JY, Lee SJ (2020) Metallothionein-3 as a multifunctional player in the control of cellular processes and diseases. Mol Brain 13:116. 
 https://doi.org/10.1186/s13041-020-00654-w
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR60" id="ref-link-section-d390719442e3879">60</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 68" title="Lee S, Martinez-Valbuena I, de Andrea CE, Villalba-Esparza M, Ilaalagan S, Couto B et al (2023) Cell-specific dysregulation of iron and oxygen homeostasis as a novel pathophysiology in PSP. Ann Neurol 93:431–445. 
 https://doi.org/10.1002/ana.26540
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR68" id="ref-link-section-d390719442e3882">68</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 93" title="Quintana C, Bellefqih S, Laval JY, Guerquin-Kern JL, Wu TD, Avila J et al (2006) Study of the localization of iron, ferritin, and hemosiderin in Alzheimer’s disease hippocampus by analytical microscopy at the subcellular level. J Struct Biol 153:42–54. 
 https://doi.org/10.1016/j.jsb.2005.11.001
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR93" id="ref-link-section-d390719442e3886">93</a>]. A recent study showed iron accumulation and dysregulation of iron and oxygen homeostasis in astrocytes and oligodendrocytes in PSP postmortem brain tissue [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 68" title="Lee S, Martinez-Valbuena I, de Andrea CE, Villalba-Esparza M, Ilaalagan S, Couto B et al (2023) Cell-specific dysregulation of iron and oxygen homeostasis as a novel pathophysiology in PSP. Ann Neurol 93:431–445. 
 https://doi.org/10.1002/ana.26540
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR68" id="ref-link-section-d390719442e3889">68</a>]. A single-soma RNA-seq study found that iron homeostasis-associated genes <i>FTL</i> and <i>FTH1</i> were highly upregulated in NFT-bearing neurons [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 85" title="Otero-Garcia M, Mahajani SU, Wakhloo D, Tang W, Xue YQ, Morabito S et al (2022) Molecular signatures underlying neurofibrillary tangle susceptibility in Alzheimer’s disease. Neuron 110(2929–2948):e2928. 
 https://doi.org/10.1016/j.neuron.2022.06.021
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR85" id="ref-link-section-d390719442e3898">85</a>]. Several genes related to endothelial cell function and secreted proteins, including <i>MT1X</i>, were differentially expressed in PSP endothelial cells, which supports the blood brain barrier breakdown seen in neurodegenerative diseases [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 117" title="Sweeney MD, Sagare AP, Zlokovic BV (2018) Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol 14:133–150. 
 https://doi.org/10.1038/nrneurol.2017.188
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR117" id="ref-link-section-d390719442e3905">117</a>]. <i>MT1X,</i> which was downregulated in PSP endothelial cells, is involved in metal homeostasis and protection against oxidative stress [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 106" title="Schulkens IA, Castricum KC, Weijers EM, Koolwijk P, Griffioen AW, Thijssen VL (2014) Expression, regulation and function of human metallothioneins in endothelial cells. J Vasc Res 51:231–238. 
 https://doi.org/10.1159/000365550
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR106" id="ref-link-section-d390719442e3911">106</a>]. PSP ChP epithelial cells downregulated <i>CLDN5</i>, the gene coding for the blood brain barrier tight junction protein claudin-5, whose dysfunction has been implicated in neurodegenerative disorders such as AD [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 41" title="Greene C, Hanley N, Campbell M (2019) Claudin-5: gatekeeper of neurological function. Fluids Barriers CNS 16:3. 
 https://doi.org/10.1186/s12987-019-0123-z
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR41" id="ref-link-section-d390719442e3917">41</a>].</p><p>PSP astrocytes and oligodendrocytes also overexpressed many AD-associated genes, including apolipoprotein E (<i>ApoE</i>), clusterin (<i>CLU</i>), and <i>QDPR.</i> In an AD single-cell RNA-seq study, <i>ApoE</i>, the most common risk factor for late-onset AD, was downregulated in AD OPC, oligodendrocyte, and astrocyte subpopulations, and upregulated in AD microglial subpopulations [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 42" title="Grubman A, Chew G, Ouyang JF, Sun G, Choo XY, McLean C et al (2019) A single-cell atlas of entorhinal cortex from individuals with Alzheimer’s disease reveals cell-type-specific gene expression regulation. Nat Neurosci 22:2087–2097. 
 https://doi.org/10.1038/s41593-019-0539-4
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR42" id="ref-link-section-d390719442e3935">42</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 74" title="Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G (2013) Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 9:106–118. 
 https://doi.org/10.1038/nrneurol.2012.263
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR74" id="ref-link-section-d390719442e3939">74</a>]. Elevated clusterin levels are reported in AD-vulnerable brain regions and an AD-protective variant of <i>CLU</i> is associated with higher expression [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 47" title="Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML et al (2009) Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet 41:1088–1093. 
 https://doi.org/10.1038/ng.440
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR47" id="ref-link-section-d390719442e3945">47</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 78" title="May PC, Johnson SA, Poirier J, Lampert-Etchells M, Finch CE (1989) Altered gene expression in Alzheimer’s disease brain tissue. Can J Neurol Sci 16:473–476. 
 https://doi.org/10.1017/s0317167100029796
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR78" id="ref-link-section-d390719442e3948">78</a>]. Clusterin has been shown to be associated with tau in AD and primary tauopathies and is preferentially expressed by an AD pathology-associated astrocyte subpopulation [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 39" title="Giannakopoulos P, Kovari E, French LE, Viard I, Hof PR, Bouras C (1998) Possible neuroprotective role of clusterin in Alzheimer’s disease: a quantitative immunocytochemical study. Acta Neuropathol 95:387–394. 
 https://doi.org/10.1007/s004010050815
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR39" id="ref-link-section-d390719442e3951">39</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 77" title="Mathys H, Davila-Velderrain J, Peng Z, Gao F, Mohammadi S, Young JZ et al (2019) Single-cell transcriptomic analysis of Alzheimer’s disease. Nature 570:332–337. 
 https://doi.org/10.1038/s41586-019-1195-2
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR77" id="ref-link-section-d390719442e3954">77</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 127" title="Wojtas AM, Carlomagno Y, Sens JP, Kang SS, Jensen TD, Kurti A et al (2020) Clusterin ameliorates tau pathology in vivo by inhibiting fibril formation. Acta Neuropathol Commun 8:210. 
 https://doi.org/10.1186/s40478-020-01079-1
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR127" id="ref-link-section-d390719442e3958">127</a>]. Additionally, <i>CLU</i> loss is associated with exacerbated tau pathology in a tauopathy mouse model [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 127" title="Wojtas AM, Carlomagno Y, Sens JP, Kang SS, Jensen TD, Kurti A et al (2020) Clusterin ameliorates tau pathology in vivo by inhibiting fibril formation. Acta Neuropathol Commun 8:210. 
 https://doi.org/10.1186/s40478-020-01079-1
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR127" id="ref-link-section-d390719442e3964">127</a>]. <i>QDPR</i> overexpression was previously identified in an AD-pathology associated white matter oligodendrocyte subpopulation [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 77" title="Mathys H, Davila-Velderrain J, Peng Z, Gao F, Mohammadi S, Young JZ et al (2019) Single-cell transcriptomic analysis of Alzheimer’s disease. Nature 570:332–337. 
 https://doi.org/10.1038/s41586-019-1195-2
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR77" id="ref-link-section-d390719442e3970">77</a>]. PSP oligodendrocytes also had decreased expression of cholesterol-synthesizing <i>DHCR24.</i> Reduced expression of <i>DHCR24</i> also occurs in the temporal cortex of AD patients [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 10" title="Bai X, Mai M, Yao K, Zhang M, Huang Y, Zhang W et al (2022) The role of DHCR24 in the pathogenesis of AD: re-cognition of the relationship between cholesterol and AD pathogenesis. Acta Neuropathol Commun 10:35. 
 https://doi.org/10.1186/s40478-022-01338-3
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR10" id="ref-link-section-d390719442e3980">10</a>]. Our PSP snRNA-seq data provides further evidence to support the role of iron accumulation and oxygen homeostasis, blood break barrier breakdown, and several AD-associated genes in neurodegenerative diseases.</p><p>Previous genetic studies have identified PSP susceptibility loci and candidate risk alleles; however, one challenge in GWAS interpretation is identifying how genetic risk manifests across cell types [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Chen JA, Chen Z, Won H, Huang AY, Lowe JK, Wojta K et al (2018) Joint genome-wide association study of progressive supranuclear palsy identifies novel susceptibility loci and genetic correlation to neurodegenerative diseases. Mol Neurodegener 13:41. 
 https://doi.org/10.1186/s13024-018-0270-8
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR20" id="ref-link-section-d390719442e3986">20</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 53" title="Hoglinger GU, Melhem NM, Dickson DW, Sleiman PM, Wang LS, Klei L et al (2011) Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet 43:699–705. 
 https://doi.org/10.1038/ng.859
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR53" id="ref-link-section-d390719442e3989">53</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 104" title="Sanchez-Contreras MY, Kouri N, Cook CN, Serie DJ, Heckman MG, Finch NA et al (2018) Replication of progressive supranuclear palsy genome-wide association study identifies SLCO1A2 and DUSP10 as new susceptibility loci. Mol Neurodegener 13:37. 
 https://doi.org/10.1186/s13024-018-0267-3
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR104" id="ref-link-section-d390719442e3992">104</a>]. We observed reduced <i>MAPT</i> expression in two neuronal clusters with reduced enrichment in PSP, and increased <i>MAPT</i> expression PSP oligodendrocytes. Other studies have suggested that the PSP <i>MAPT-</i>related risk does not manifest as differences in total tau mRNA expression [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 120" title="Trabzuni D, Wray S, Vandrovcova J, Ramasamy A, Walker R, Smith C et al (2012) MAPT expression and splicing is differentially regulated by brain region: relation to genotype and implication for tauopathies. Hum Mol Genet 21:4094–4103. 
 https://doi.org/10.1093/hmg/dds238
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR120" id="ref-link-section-d390719442e4005">120</a>]. Although the <i>MAPT</i> locus is the most strongly associated genetic risk factor, the mechanism is still unclear, but the extent to which altered expression of tau mRNA contributes continues to be an active and complex area of research [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 34" title="Forrest SL, Lee S, Nassir N, Martinez-Valbuena I, Sackmann V, Li J et al (2023) Cell-specific MAPT gene expression is preserved in neuronal and glial tau cytopathologies in progressive supranuclear palsy. Acta Neuropathol 146:395–414. 
 https://doi.org/10.1007/s00401-023-02604-x
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR34" id="ref-link-section-d390719442e4011">34</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 98" title="Ressler HW, Humphrey J, Vialle RA, Babrowicz B, Kandoi S, Raj T et al (2024) MAPT haplotype-associated transcriptomic changes in progressive supranuclear palsy. Acta Neuropathol Commun 12:135. 
 https://doi.org/10.1186/s40478-024-01839-3
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR98" id="ref-link-section-d390719442e4014">98</a>]. The PERK-encoding gene <i>EIF2AK3</i> was not upregulated in any PSP neuronal clusters but was increased in PSP oligodendrocytes. Tau aggregation and pharmacologic UPR activation in vivo altered the expression of PERK-regulated genes but not the expression of the PERK-encoding gene (<i>EIF2AK3)</i> [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 87" title="Park G, Xu K, Chea L, Kim K, Safarta L, Song KH et al (2023) Neurodegeneration risk factor, EIF2AK3 (PERK), influences tau protein aggregation. J Biol Chem 299:102821. 
 https://doi.org/10.1016/j.jbc.2022.102821
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR87" id="ref-link-section-d390719442e4024">87</a>]. This suggests that transcriptional changes during tau-induced UPR activation may be downstream of or not change <i>EIF2AK3</i> expression. Further examination of candidate risk genes in cellular systems is needed, such as PSP patient-derived iPSC models of different cell types, which retain the diseased human genome.</p><p>A limitation of our study is the small sample size and heterogeneity of PSP pathology in patient samples. While this heterogeneity is likely representative of the spectrum of PSP disease severity, whether there are any significant associations of particular neuronal subpopulations with tau pathology requires systematic stratification of the PSP variants and further analysis with a larger cohort of individuals with similar PSP tau pathology. We performed our analysis in critical diencephalic structures, including those that are selectively vulnerable in PSP, but the sampling strategy used in this study has challenges in precisely targeting this region especially in diseased brain tissue. Thus, our sequencing therefore included adjacent thalamic nuclei in addition to the subthalamic nucleus and this should be taken into account when interpreting the results. Additionally, we performed snRNAseq and histological assessments on different sides of the brain, and therefore cannot account for potential asymmetrical involvement, but this is not a prominent feature of PSP [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 26" title="Dickson DW, Rademakers R, Hutton ML (2007) Progressive supranuclear palsy: pathology and genetics. Brain Pathol 17:74–82. 
 https://doi.org/10.1111/j.1750-3639.2007.00054.x
 
 " href="/article/10.1007/s00401-024-02823-w#ref-CR26" id="ref-link-section-d390719442e4034">26</a>]. Further, the number of transcripts from PSP and control cases differed due to mitochondrial rate quality control processing. Without quality control processing, the number of transcripts from PSP cases was lower; however, these may have arisen from the neurodegenerative changes that typify PSP, as PSP is a neurodegenerative disease with greater proportion of apoptotic cells than healthy control samples. Due to the small sample size, our differential expression analysis method does not consider biological replicates and we applied a nominal <i>p</i> value cutoff. However, our discovery findings were validated in an independent snRNA-seq replication cohort with a larger sample size and more stringent cutoffs for FDR adjusted <i>p</i> value. We also validated our main finding histologically. Nevertheless, further studies including larger cohorts, more brain regions, and other orthogonal approaches (e.g., qPCR, proteomics, immunoblots, etc.) are needed to account for biological replication and fully profile transcriptomic changes in affected cell types in PSP.</p><p>In conclusion, our study contributes a novel characterization of cell-type-specific changes in PSP using snRNA-seq and provides transcriptomic and histological evidence for the involvement of adaptive stress pathways in PSP pathogenesis in vulnerable cell types. Understanding the differences in gene expression between affected and unaffected cell types may reveal molecular mechanisms underlying vulnerability and resistance to neurodegeneration. These results also highlight the need for detailed functional characterization of multiple cell types to develop better models and therapeutic modalities for PSP. Our data will inform future studies to identify the mechanisms of tau accumulation, degeneration, and repair in PSP.</p></div></div></section> </div> <section data-title="Data availability"><div class="c-article-section" id="data-availability-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="data-availability">Data availability</h2><div class="c-article-section__content" id="data-availability-content"> <p>The single-nucleus RNA-sequencing dataset generated for this study has been shared online at Sage Bionetworks (Synapse.org ID: SYN62145232).</p> </div></div></section><div id="MagazineFulltextArticleBodySuffix"><section aria-labelledby="Bib1" data-title="References"><div class="c-article-section" id="Bib1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Bib1">References</h2><div class="c-article-section__content" id="Bib1-content"><div data-container-section="references"><ol class="c-article-references" data-track-component="outbound reference" data-track-context="references section"><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="1."><p class="c-article-references__text" id="ref-CR1">Abisambra JF, Jinwal UK, Blair LJ, O’Leary JC 3rd, Li Q, Brady S et al (2013) Tau accumulation activates the unfolded protein response by impairing endoplasmic reticulum-associated degradation. J Neurosci 33:9498–9507. <a href="https://doi.org/10.1523/JNEUROSCI.5397-12.2013" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1523/JNEUROSCI.5397-12.2013">https://doi.org/10.1523/JNEUROSCI.5397-12.2013</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1523/JNEUROSCI.5397-12.2013" data-track-item_id="10.1523/JNEUROSCI.5397-12.2013" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1523%2FJNEUROSCI.5397-12.2013" aria-label="Article reference 1" data-doi="10.1523/JNEUROSCI.5397-12.2013">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23719816" aria-label="PubMed reference 1">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733249" aria-label="PubMed Central reference 1">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC3sXovFeqsb4%3D" aria-label="CAS reference 1">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 1" href="http://scholar.google.com/scholar_lookup?&title=Tau%20accumulation%20activates%20the%20unfolded%20protein%20response%20by%20impairing%20endoplasmic%20reticulum-associated%20degradation&journal=J%20Neurosci&doi=10.1523%2FJNEUROSCI.5397-12.2013&volume=33&pages=9498-9507&publication_year=2013&author=Abisambra%2CJF&author=Jinwal%2CUK&author=Blair%2CLJ&author=O%27Leary%2CJC&author=Li%2CQ&author=Brady%2CS&author=Wang%2CL&author=Guidi%2CCE&author=Zhang%2CB&author=Nordhues%2CBA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="2."><p class="c-article-references__text" id="ref-CR2">Ahmed Z, Bigio EH, Budka H, Dickson DW, Ferrer I, Ghetti B et al (2013) Globular glial tauopathies (GGT): consensus recommendations. Acta Neuropathol 126:537–544. <a href="https://doi.org/10.1007/s00401-013-1171-0" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1007/s00401-013-1171-0">https://doi.org/10.1007/s00401-013-1171-0</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1007/s00401-013-1171-0" data-track-item_id="10.1007/s00401-013-1171-0" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1007/s00401-013-1171-0" aria-label="Article reference 2" data-doi="10.1007/s00401-013-1171-0">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23995422" aria-label="PubMed reference 2">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3914659" aria-label="PubMed Central reference 2">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 2" href="http://scholar.google.com/scholar_lookup?&title=Globular%20glial%20tauopathies%20%28GGT%29%3A%20consensus%20recommendations&journal=Acta%20Neuropathol&doi=10.1007%2Fs00401-013-1171-0&volume=126&pages=537-544&publication_year=2013&author=Ahmed%2CZ&author=Bigio%2CEH&author=Budka%2CH&author=Dickson%2CDW&author=Ferrer%2CI&author=Ghetti%2CB&author=Giaccone%2CG&author=Hatanpaa%2CKJ&author=Holton%2CJL&author=Josephs%2CKA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="3."><p class="c-article-references__text" id="ref-CR3">Ajoolabady A, Lindholm D, Ren J, Pratico D (2022) ER stress and UPR in Alzheimer’s disease: mechanisms, pathogenesis, treatments. Cell Death Dis 13:706. <a href="https://doi.org/10.1038/s41419-022-05153-5" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1038/s41419-022-05153-5">https://doi.org/10.1038/s41419-022-05153-5</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/s41419-022-05153-5" data-track-item_id="10.1038/s41419-022-05153-5" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fs41419-022-05153-5" aria-label="Article reference 3" data-doi="10.1038/s41419-022-05153-5">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=35970828" aria-label="PubMed reference 3">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9378716" aria-label="PubMed Central reference 3">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 3" href="http://scholar.google.com/scholar_lookup?&title=ER%20stress%20and%20UPR%20in%20Alzheimer%27s%20disease%3A%20mechanisms%2C%20pathogenesis%2C%20treatments&journal=Cell%20Death%20Dis&doi=10.1038%2Fs41419-022-05153-5&volume=13&publication_year=2022&author=Ajoolabady%2CA&author=Lindholm%2CD&author=Ren%2CJ&author=Pratico%2CD"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="4."><p class="c-article-references__text" id="ref-CR4">Al-Dalahmah O, Sosunov AA, Shaik A, Ofori K, Liu Y, Vonsattel JP et al (2020) Single-nucleus RNA-seq identifies Huntington disease astrocyte states. Acta Neuropathol Commun 8:19. <a href="https://doi.org/10.1186/s40478-020-0880-6" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1186/s40478-020-0880-6">https://doi.org/10.1186/s40478-020-0880-6</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/s40478-020-0880-6" data-track-item_id="10.1186/s40478-020-0880-6" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/s40478-020-0880-6" aria-label="Article reference 4" data-doi="10.1186/s40478-020-0880-6">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32070434" aria-label="PubMed reference 4">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029580" aria-label="PubMed Central reference 4">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXltFeksr0%3D" aria-label="CAS reference 4">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 4" href="http://scholar.google.com/scholar_lookup?&title=Single-nucleus%20RNA-seq%20identifies%20Huntington%20disease%20astrocyte%20states&journal=Acta%20Neuropathol%20Commun&doi=10.1186%2Fs40478-020-0880-6&volume=8&publication_year=2020&author=Al-Dalahmah%2CO&author=Sosunov%2CAA&author=Shaik%2CA&author=Ofori%2CK&author=Liu%2CY&author=Vonsattel%2CJP&author=Adorjan%2CI&author=Menon%2CV&author=Goldman%2CJE"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="5."><p class="c-article-references__text" id="ref-CR5">Alafuzoff I, Arzberger T, Al-Sarraj S, Bodi I, Bogdanovic N, Braak H et al (2008) Staging of neurofibrillary pathology in Alzheimer’s disease: a study of the BrainNet Europe consortium. Brain Pathol 18:484–496. <a href="https://doi.org/10.1111/j.1750-3639.2008.00147.x" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1111/j.1750-3639.2008.00147.x">https://doi.org/10.1111/j.1750-3639.2008.00147.x</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1111/j.1750-3639.2008.00147.x" data-track-item_id="10.1111/j.1750-3639.2008.00147.x" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1111%2Fj.1750-3639.2008.00147.x" aria-label="Article reference 5" data-doi="10.1111/j.1750-3639.2008.00147.x">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=18371174" aria-label="PubMed reference 5">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2659377" aria-label="PubMed Central reference 5">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 5" href="http://scholar.google.com/scholar_lookup?&title=Staging%20of%20neurofibrillary%20pathology%20in%20Alzheimer%27s%20disease%3A%20a%20study%20of%20the%20BrainNet%20Europe%20consortium&journal=Brain%20Pathol&doi=10.1111%2Fj.1750-3639.2008.00147.x&volume=18&pages=484-496&publication_year=2008&author=Alafuzoff%2CI&author=Arzberger%2CT&author=Al-Sarraj%2CS&author=Bodi%2CI&author=Bogdanovic%2CN&author=Braak%2CH&author=Bugiani%2CO&author=Del-Tredici%2CK&author=Ferrer%2CI&author=Gelpi%2CE"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="6."><p class="c-article-references__text" id="ref-CR6">Allen M, Burgess JD, Ballard T, Serie D, Wang X, Younkin CS et al (2016) Gene expression, methylation and neuropathology correlations at progressive supranuclear palsy risk loci. Acta Neuropathol 132:197–211. <a href="https://doi.org/10.1007/s00401-016-1576-7" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1007/s00401-016-1576-7">https://doi.org/10.1007/s00401-016-1576-7</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1007/s00401-016-1576-7" data-track-item_id="10.1007/s00401-016-1576-7" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1007/s00401-016-1576-7" aria-label="Article reference 6" data-doi="10.1007/s00401-016-1576-7">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=27115769" aria-label="PubMed reference 6">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947429" aria-label="PubMed Central reference 6">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC28XhsVGhu7%2FM" aria-label="CAS reference 6">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 6" href="http://scholar.google.com/scholar_lookup?&title=Gene%20expression%2C%20methylation%20and%20neuropathology%20correlations%20at%20progressive%20supranuclear%20palsy%20risk%20loci&journal=Acta%20Neuropathol&doi=10.1007%2Fs00401-016-1576-7&volume=132&pages=197-211&publication_year=2016&author=Allen%2CM&author=Burgess%2CJD&author=Ballard%2CT&author=Serie%2CD&author=Wang%2CX&author=Younkin%2CCS&author=Sun%2CZ&author=Kouri%2CN&author=Baheti%2CS&author=Wang%2CC"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="7."><p class="c-article-references__text" id="ref-CR7">Allen M, Wang X, Serie DJ, Strickland SL, Burgess JD, Koga S et al (2018) Divergent brain gene expression patterns associate with distinct cell-specific tau neuropathology traits in progressive supranuclear palsy. Acta Neuropathol 136:709–727. <a href="https://doi.org/10.1007/s00401-018-1900-5" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1007/s00401-018-1900-5">https://doi.org/10.1007/s00401-018-1900-5</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1007/s00401-018-1900-5" data-track-item_id="10.1007/s00401-018-1900-5" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1007/s00401-018-1900-5" aria-label="Article reference 7" data-doi="10.1007/s00401-018-1900-5">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=30136084" aria-label="PubMed reference 7">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208732" aria-label="PubMed Central reference 7">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC1cXhsFOjsrrI" aria-label="CAS reference 7">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 7" href="http://scholar.google.com/scholar_lookup?&title=Divergent%20brain%20gene%20expression%20patterns%20associate%20with%20distinct%20cell-specific%20tau%20neuropathology%20traits%20in%20progressive%20supranuclear%20palsy&journal=Acta%20Neuropathol&doi=10.1007%2Fs00401-018-1900-5&volume=136&pages=709-727&publication_year=2018&author=Allen%2CM&author=Wang%2CX&author=Serie%2CDJ&author=Strickland%2CSL&author=Burgess%2CJD&author=Koga%2CS&author=Younkin%2CCS&author=Nguyen%2CTT&author=Malphrus%2CKG&author=Lincoln%2CSJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="8."><p class="c-article-references__text" id="ref-CR8">Andrews S (2010) FastQC: a quality control tool for high throughput sequence data <a href="http://www.bioinformatics.babraham.ac.uk/projects/fastqc" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="http://www.bioinformatics.babraham.ac.uk/projects/fastqc">http://www.bioinformatics.babraham.ac.uk/projects/fastqc</a></p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="9."><p class="c-article-references__text" id="ref-CR9">Aran D, Looney AP, Liu L, Wu E, Fong V, Hsu A et al (2019) Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage. Nat Immunol 20:163–172. <a href="https://doi.org/10.1038/s41590-018-0276-y" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1038/s41590-018-0276-y">https://doi.org/10.1038/s41590-018-0276-y</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/s41590-018-0276-y" data-track-item_id="10.1038/s41590-018-0276-y" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fs41590-018-0276-y" aria-label="Article reference 9" data-doi="10.1038/s41590-018-0276-y">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=30643263" aria-label="PubMed reference 9">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340744" aria-label="PubMed Central reference 9">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC1MXlvFSgu7k%3D" aria-label="CAS reference 9">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 9" href="http://scholar.google.com/scholar_lookup?&title=Reference-based%20analysis%20of%20lung%20single-cell%20sequencing%20reveals%20a%20transitional%20profibrotic%20macrophage&journal=Nat%20Immunol&doi=10.1038%2Fs41590-018-0276-y&volume=20&pages=163-172&publication_year=2019&author=Aran%2CD&author=Looney%2CAP&author=Liu%2CL&author=Wu%2CE&author=Fong%2CV&author=Hsu%2CA&author=Chak%2CS&author=Naikawadi%2CRP&author=Wolters%2CPJ&author=Abate%2CAR"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="10."><p class="c-article-references__text" id="ref-CR10">Bai X, Mai M, Yao K, Zhang M, Huang Y, Zhang W et al (2022) The role of DHCR24 in the pathogenesis of AD: re-cognition of the relationship between cholesterol and AD pathogenesis. Acta Neuropathol Commun 10:35. <a href="https://doi.org/10.1186/s40478-022-01338-3" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1186/s40478-022-01338-3">https://doi.org/10.1186/s40478-022-01338-3</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/s40478-022-01338-3" data-track-item_id="10.1186/s40478-022-01338-3" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/s40478-022-01338-3" aria-label="Article reference 10" data-doi="10.1186/s40478-022-01338-3">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=35296367" aria-label="PubMed reference 10">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8925223" aria-label="PubMed Central reference 10">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB38XhsVKitrvL" aria-label="CAS reference 10">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 10" href="http://scholar.google.com/scholar_lookup?&title=The%20role%20of%20DHCR24%20in%20the%20pathogenesis%20of%20AD%3A%20re-cognition%20of%20the%20relationship%20between%20cholesterol%20and%20AD%20pathogenesis&journal=Acta%20Neuropathol%20Commun&doi=10.1186%2Fs40478-022-01338-3&volume=10&publication_year=2022&author=Bai%2CX&author=Mai%2CM&author=Yao%2CK&author=Zhang%2CM&author=Huang%2CY&author=Zhang%2CW&author=Guo%2CX&author=Xu%2CY&author=Zhang%2CY&author=Qurban%2CA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="11."><p class="c-article-references__text" id="ref-CR11">Batenburg KL, Kasri NN, Heine VM, Scheper W (2023) Intraneuronal tau aggregation induces the integrated stress response in astrocytes. J Mol Cell Biol. <a href="https://doi.org/10.1093/jmcb/mjac071" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1093/jmcb/mjac071">https://doi.org/10.1093/jmcb/mjac071</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1093/jmcb/mjac071" data-track-item_id="10.1093/jmcb/mjac071" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1093%2Fjmcb%2Fmjac071" aria-label="Article reference 11" data-doi="10.1093/jmcb/mjac071">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=36520068" aria-label="PubMed reference 11">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 11" href="http://scholar.google.com/scholar_lookup?&title=Intraneuronal%20tau%20aggregation%20induces%20the%20integrated%20stress%20response%20in%20astrocytes&journal=J%20Mol%20Cell%20Biol&doi=10.1093%2Fjmcb%2Fmjac071&publication_year=2023&author=Batenburg%2CKL&author=Kasri%2CNN&author=Heine%2CVM&author=Scheper%2CW"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="12."><p class="c-article-references__text" id="ref-CR12">Baudier J, Cole RD (1987) Phosphorylation of tau proteins to a state like that in Alzheimer’s brain is catalyzed by a calcium/calmodulin-dependent kinase and modulated by phospholipids. J Biol Chem 262:17577–17583</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/S0021-9258(18)45420-8" data-track-item_id="10.1016/S0021-9258(18)45420-8" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2FS0021-9258%2818%2945420-8" aria-label="Article reference 12" data-doi="10.1016/S0021-9258(18)45420-8">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=3121601" aria-label="PubMed reference 12">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DyaL1cXkt1Cn" aria-label="CAS reference 12">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 12" href="http://scholar.google.com/scholar_lookup?&title=Phosphorylation%20of%20tau%20proteins%20to%20a%20state%20like%20that%20in%20Alzheimer%27s%20brain%20is%20catalyzed%20by%20a%20calcium%2Fcalmodulin-dependent%20kinase%20and%20modulated%20by%20phospholipids&journal=J%20Biol%20Chem&doi=10.1016%2FS0021-9258%2818%2945420-8&volume=262&pages=17577-17583&publication_year=1987&author=Baudier%2CJ&author=Cole%2CRD"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="13."><p class="c-article-references__text" id="ref-CR13">Bezprozvanny I, Mattson MP (2008) Neuronal calcium mishandling and the pathogenesis of Alzheimer’s disease. Trends Neurosci 31:454–463. <a href="https://doi.org/10.1016/j.tins.2008.06.005" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1016/j.tins.2008.06.005">https://doi.org/10.1016/j.tins.2008.06.005</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.tins.2008.06.005" data-track-item_id="10.1016/j.tins.2008.06.005" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.tins.2008.06.005" aria-label="Article reference 13" data-doi="10.1016/j.tins.2008.06.005">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=18675468" aria-label="PubMed reference 13">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2566585" aria-label="PubMed Central reference 13">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD1cXhtVKnurzI" aria-label="CAS reference 13">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 13" href="http://scholar.google.com/scholar_lookup?&title=Neuronal%20calcium%20mishandling%20and%20the%20pathogenesis%20of%20Alzheimer%27s%20disease&journal=Trends%20Neurosci&doi=10.1016%2Fj.tins.2008.06.005&volume=31&pages=454-463&publication_year=2008&author=Bezprozvanny%2CI&author=Mattson%2CMP"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="14."><p class="c-article-references__text" id="ref-CR14">Bik-Multanowski M, Pietrzyk JJ, Midro A (2015) MTRNR2L12: A candidate blood marker of early Alzheimer’s disease-like dementia in adults with down syndrome. J Alzheimers Dis 46:145–150. <a href="https://doi.org/10.3233/JAD-143030" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.3233/JAD-143030">https://doi.org/10.3233/JAD-143030</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.3233/JAD-143030" data-track-item_id="10.3233/JAD-143030" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.3233%2FJAD-143030" aria-label="Article reference 14" data-doi="10.3233/JAD-143030">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=25720405" aria-label="PubMed reference 14">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878308" aria-label="PubMed Central reference 14">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC2MXpsVWjt7w%3D" aria-label="CAS reference 14">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 14" href="http://scholar.google.com/scholar_lookup?&title=MTRNR2L12%3A%20A%20candidate%20blood%20marker%20of%20early%20Alzheimer%27s%20disease-like%20dementia%20in%20adults%20with%20down%20syndrome&journal=J%20Alzheimers%20Dis&doi=10.3233%2FJAD-143030&volume=46&pages=145-150&publication_year=2015&author=Bik-Multanowski%2CM&author=Pietrzyk%2CJJ&author=Midro%2CA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="15."><p class="c-article-references__text" id="ref-CR15">Bolger AM, Lohse M, Usadel B (2014) Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 30:2114–2120. <a href="https://doi.org/10.1093/bioinformatics/btu170" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1093/bioinformatics/btu170">https://doi.org/10.1093/bioinformatics/btu170</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1093/bioinformatics/btu170" data-track-item_id="10.1093/bioinformatics/btu170" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1093%2Fbioinformatics%2Fbtu170" aria-label="Article reference 15" data-doi="10.1093/bioinformatics/btu170">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=24695404" aria-label="PubMed reference 15">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4103590" aria-label="PubMed Central reference 15">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC2cXht1Sqt7nP" aria-label="CAS reference 15">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 15" href="http://scholar.google.com/scholar_lookup?&title=Trimmomatic%3A%20a%20flexible%20trimmer%20for%20Illumina%20sequence%20data&journal=Bioinformatics&doi=10.1093%2Fbioinformatics%2Fbtu170&volume=30&pages=2114-2120&publication_year=2014&author=Bolger%2CAM&author=Lohse%2CM&author=Usadel%2CB"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="16."><p class="c-article-references__text" id="ref-CR16">Boxer AL, Yu JT, Golbe LI, Litvan I, Lang AE, Hoglinger GU (2017) Advances in progressive supranuclear palsy: new diagnostic criteria, biomarkers, and therapeutic approaches. Lancet Neurol 16:552–563. <a href="https://doi.org/10.1016/S1474-4422(17)30157-6" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1016/S1474-4422(17)30157-6">https://doi.org/10.1016/S1474-4422(17)30157-6</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/S1474-4422(17)30157-6" data-track-item_id="10.1016/S1474-4422(17)30157-6" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2FS1474-4422%2817%2930157-6" aria-label="Article reference 16" data-doi="10.1016/S1474-4422(17)30157-6">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=28653647" aria-label="PubMed reference 16">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5802400" aria-label="PubMed Central reference 16">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 16" href="http://scholar.google.com/scholar_lookup?&title=Advances%20in%20progressive%20supranuclear%20palsy%3A%20new%20diagnostic%20criteria%2C%20biomarkers%2C%20and%20therapeutic%20approaches&journal=Lancet%20Neurol&doi=10.1016%2FS1474-4422%2817%2930157-6&volume=16&pages=552-563&publication_year=2017&author=Boxer%2CAL&author=Yu%2CJT&author=Golbe%2CLI&author=Litvan%2CI&author=Lang%2CAE&author=Hoglinger%2CGU"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="17."><p class="c-article-references__text" id="ref-CR17">Brigstock DR (2002) Regulation of angiogenesis and endothelial cell function by connective tissue growth factor (CTGF) and cysteine-rich 61 (CYR61). Angiogenesis 5:153–165. <a href="https://doi.org/10.1023/a:1023823803510" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1023/a:1023823803510">https://doi.org/10.1023/a:1023823803510</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1023/a:1023823803510" data-track-item_id="10.1023/a:1023823803510" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1023%2Fa%3A1023823803510" aria-label="Article reference 17" data-doi="10.1023/a:1023823803510">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=12831056" aria-label="PubMed reference 17">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD3sXjvVagtrg%3D" aria-label="CAS reference 17">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 17" href="http://scholar.google.com/scholar_lookup?&title=Regulation%20of%20angiogenesis%20and%20endothelial%20cell%20function%20by%20connective%20tissue%20growth%20factor%20%28CTGF%29%20and%20cysteine-rich%2061%20%28CYR61%29&journal=Angiogenesis&doi=10.1023%2Fa%3A1023823803510&volume=5&pages=153-165&publication_year=2002&author=Brigstock%2CDR"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="18."><p class="c-article-references__text" id="ref-CR18">Broad KD, Curley JP, Keverne EB (2009) Increased apoptosis during neonatal brain development underlies the adult behavioral deficits seen in mice lacking a functional paternally expressed gene 3 (Peg3). Dev Neurobiol 69:314–325. <a href="https://doi.org/10.1002/dneu.20702" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1002/dneu.20702">https://doi.org/10.1002/dneu.20702</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1002/dneu.20702" data-track-item_id="10.1002/dneu.20702" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2Fdneu.20702" aria-label="Article reference 18" data-doi="10.1002/dneu.20702">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=19224563" aria-label="PubMed reference 18">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD1MXkvVGqurY%3D" aria-label="CAS reference 18">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 18" href="http://scholar.google.com/scholar_lookup?&title=Increased%20apoptosis%20during%20neonatal%20brain%20development%20underlies%20the%20adult%20behavioral%20deficits%20seen%20in%20mice%20lacking%20a%20functional%20paternally%20expressed%20gene%203%20%28Peg3%29&journal=Dev%20Neurobiol&doi=10.1002%2Fdneu.20702&volume=69&pages=314-325&publication_year=2009&author=Broad%2CKD&author=Curley%2CJP&author=Keverne%2CEB"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="19."><p class="c-article-references__text" id="ref-CR19">Bruch J, Xu H, Rosler TW, De Andrade A, Kuhn PH, Lichtenthaler SF et al (2017) PERK activation mitigates tau pathology in vitro and in vivo. EMBO Mol Med 9:371–384. <a href="https://doi.org/10.15252/emmm.201606664" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.15252/emmm.201606664">https://doi.org/10.15252/emmm.201606664</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.15252/emmm.201606664" data-track-item_id="10.15252/emmm.201606664" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.15252%2Femmm.201606664" aria-label="Article reference 19" data-doi="10.15252/emmm.201606664">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=28148553" aria-label="PubMed reference 19">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5331260" aria-label="PubMed Central reference 19">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC2sXhvV2jsrY%3D" aria-label="CAS reference 19">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 19" href="http://scholar.google.com/scholar_lookup?&title=PERK%20activation%20mitigates%20tau%20pathology%20in%20vitro%20and%20in%20vivo&journal=EMBO%20Mol%20Med&doi=10.15252%2Femmm.201606664&volume=9&pages=371-384&publication_year=2017&author=Bruch%2CJ&author=Xu%2CH&author=Rosler%2CTW&author=Andrade%2CA&author=Kuhn%2CPH&author=Lichtenthaler%2CSF&author=Arzberger%2CT&author=Winklhofer%2CKF&author=Muller%2CU&author=Hoglinger%2CGU"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="20."><p class="c-article-references__text" id="ref-CR20">Chen JA, Chen Z, Won H, Huang AY, Lowe JK, Wojta K et al (2018) Joint genome-wide association study of progressive supranuclear palsy identifies novel susceptibility loci and genetic correlation to neurodegenerative diseases. Mol Neurodegener 13:41. <a href="https://doi.org/10.1186/s13024-018-0270-8" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1186/s13024-018-0270-8">https://doi.org/10.1186/s13024-018-0270-8</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/s13024-018-0270-8" data-track-item_id="10.1186/s13024-018-0270-8" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/s13024-018-0270-8" aria-label="Article reference 20" data-doi="10.1186/s13024-018-0270-8">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=30089514" aria-label="PubMed reference 20">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6083608" aria-label="PubMed Central reference 20">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC1MXjt1Ohtr4%3D" aria-label="CAS reference 20">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 20" href="http://scholar.google.com/scholar_lookup?&title=Joint%20genome-wide%20association%20study%20of%20progressive%20supranuclear%20palsy%20identifies%20novel%20susceptibility%20loci%20and%20genetic%20correlation%20to%20neurodegenerative%20diseases&journal=Mol%20Neurodegener&doi=10.1186%2Fs13024-018-0270-8&volume=13&publication_year=2018&author=Chen%2CJA&author=Chen%2CZ&author=Won%2CH&author=Huang%2CAY&author=Lowe%2CJK&author=Wojta%2CK&author=Yokoyama%2CJS&author=Bensimon%2CG&author=Leigh%2CPN&author=Payan%2CC"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="21."><p class="c-article-references__text" id="ref-CR21">Colbran RJ (2004) Protein phosphatases and calcium/calmodulin-dependent protein kinase II-dependent synaptic plasticity. J Neurosci 24:8404–8409. <a href="https://doi.org/10.1523/JNEUROSCI.3602-04.2004" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1523/JNEUROSCI.3602-04.2004">https://doi.org/10.1523/JNEUROSCI.3602-04.2004</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1523/JNEUROSCI.3602-04.2004" data-track-item_id="10.1523/JNEUROSCI.3602-04.2004" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1523%2FJNEUROSCI.3602-04.2004" aria-label="Article reference 21" data-doi="10.1523/JNEUROSCI.3602-04.2004">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=15456812" aria-label="PubMed reference 21">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6729910" aria-label="PubMed Central reference 21">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD2cXosVOjsbk%3D" aria-label="CAS reference 21">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 21" href="http://scholar.google.com/scholar_lookup?&title=Protein%20phosphatases%20and%20calcium%2Fcalmodulin-dependent%20protein%20kinase%20II-dependent%20synaptic%20plasticity&journal=J%20Neurosci&doi=10.1523%2FJNEUROSCI.3602-04.2004&volume=24&pages=8404-8409&publication_year=2004&author=Colbran%2CRJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="22."><p class="c-article-references__text" id="ref-CR22">Costa-Mattioli M, Walter P (2020) The integrated stress response: from mechanism to disease. Science. <a href="https://doi.org/10.1126/science.aat5314" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1126/science.aat5314">https://doi.org/10.1126/science.aat5314</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1126/science.aat5314" data-track-item_id="10.1126/science.aat5314" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1126%2Fscience.aat5314" aria-label="Article reference 22" data-doi="10.1126/science.aat5314">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32327570" aria-label="PubMed reference 22">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8997189" aria-label="PubMed Central reference 22">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 22" href="http://scholar.google.com/scholar_lookup?&title=The%20integrated%20stress%20response%3A%20from%20mechanism%20to%20disease&journal=Science&doi=10.1126%2Fscience.aat5314&publication_year=2020&author=Costa-Mattioli%2CM&author=Walter%2CP"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="23."><p class="c-article-references__text" id="ref-CR23">Dexter DT, Carayon A, Javoy-Agid F, Agid Y, Wells FR, Daniel SE et al (1991) Alterations in the levels of iron, ferritin and other trace metals in Parkinson’s disease and other neurodegenerative diseases affecting the basal ganglia. Brain 114(Pt 4):1953–1975. <a href="https://doi.org/10.1093/brain/114.4.1953" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1093/brain/114.4.1953">https://doi.org/10.1093/brain/114.4.1953</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1093/brain/114.4.1953" data-track-item_id="10.1093/brain/114.4.1953" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1093%2Fbrain%2F114.4.1953" aria-label="Article reference 23" data-doi="10.1093/brain/114.4.1953">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=1832073" aria-label="PubMed reference 23">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 23" href="http://scholar.google.com/scholar_lookup?&title=Alterations%20in%20the%20levels%20of%20iron%2C%20ferritin%20and%20other%20trace%20metals%20in%20Parkinson%27s%20disease%20and%20other%20neurodegenerative%20diseases%20affecting%20the%20basal%20ganglia&journal=Brain&doi=10.1093%2Fbrain%2F114.4.1953&volume=114&issue=Pt%204&pages=1953-1975&publication_year=1991&author=Dexter%2CDT&author=Carayon%2CA&author=Javoy-Agid%2CF&author=Agid%2CY&author=Wells%2CFR&author=Daniel%2CSE&author=Lees%2CAJ&author=Jenner%2CP&author=Marsden%2CCD"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="24."><p class="c-article-references__text" id="ref-CR24">Dickson DW, Ahmed Z, Algom AA, Tsuboi Y, Josephs KA (2010) Neuropathology of variants of progressive supranuclear palsy. Curr Opin Neurol 23:394–400. <a href="https://doi.org/10.1097/WCO.0b013e32833be924" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1097/WCO.0b013e32833be924">https://doi.org/10.1097/WCO.0b013e32833be924</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1097/WCO.0b013e32833be924" data-track-item_id="10.1097/WCO.0b013e32833be924" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1097%2FWCO.0b013e32833be924" aria-label="Article reference 24" data-doi="10.1097/WCO.0b013e32833be924">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=20610990" aria-label="PubMed reference 24">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 24" href="http://scholar.google.com/scholar_lookup?&title=Neuropathology%20of%20variants%20of%20progressive%20supranuclear%20palsy&journal=Curr%20Opin%20Neurol&doi=10.1097%2FWCO.0b013e32833be924&volume=23&pages=394-400&publication_year=2010&author=Dickson%2CDW&author=Ahmed%2CZ&author=Algom%2CAA&author=Tsuboi%2CY&author=Josephs%2CKA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="25."><p class="c-article-references__text" id="ref-CR25">Dickson DW, Bergeron C, Chin SS, Duyckaerts C, Horoupian D, Ikeda K et al (2002) Office of rare diseases neuropathologic criteria for corticobasal degeneration. J Neuropathol Exp Neurol 61:935–946. <a href="https://doi.org/10.1093/jnen/61.11.935" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1093/jnen/61.11.935">https://doi.org/10.1093/jnen/61.11.935</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1093/jnen/61.11.935" data-track-item_id="10.1093/jnen/61.11.935" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1093%2Fjnen%2F61.11.935" aria-label="Article reference 25" data-doi="10.1093/jnen/61.11.935">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=12430710" aria-label="PubMed reference 25">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:STN:280:DC%2BD38nntVSkuw%3D%3D" aria-label="CAS reference 25">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 25" href="http://scholar.google.com/scholar_lookup?&title=Office%20of%20rare%20diseases%20neuropathologic%20criteria%20for%20corticobasal%20degeneration&journal=J%20Neuropathol%20Exp%20Neurol&doi=10.1093%2Fjnen%2F61.11.935&volume=61&pages=935-946&publication_year=2002&author=Dickson%2CDW&author=Bergeron%2CC&author=Chin%2CSS&author=Duyckaerts%2CC&author=Horoupian%2CD&author=Ikeda%2CK&author=Jellinger%2CK&author=Lantos%2CPL&author=Lippa%2CCF&author=Mirra%2CSS"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="26."><p class="c-article-references__text" id="ref-CR26">Dickson DW, Rademakers R, Hutton ML (2007) Progressive supranuclear palsy: pathology and genetics. Brain Pathol 17:74–82. <a href="https://doi.org/10.1111/j.1750-3639.2007.00054.x" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1111/j.1750-3639.2007.00054.x">https://doi.org/10.1111/j.1750-3639.2007.00054.x</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1111/j.1750-3639.2007.00054.x" data-track-item_id="10.1111/j.1750-3639.2007.00054.x" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1111%2Fj.1750-3639.2007.00054.x" aria-label="Article reference 26" data-doi="10.1111/j.1750-3639.2007.00054.x">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=17493041" aria-label="PubMed reference 26">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095545" aria-label="PubMed Central reference 26">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD2sXkvFShsr4%3D" aria-label="CAS reference 26">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 26" href="http://scholar.google.com/scholar_lookup?&title=Progressive%20supranuclear%20palsy%3A%20pathology%20and%20genetics&journal=Brain%20Pathol&doi=10.1111%2Fj.1750-3639.2007.00054.x&volume=17&pages=74-82&publication_year=2007&author=Dickson%2CDW&author=Rademakers%2CR&author=Hutton%2CML"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="27."><p class="c-article-references__text" id="ref-CR27">Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S et al (2013) STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29:15–21. <a href="https://doi.org/10.1093/bioinformatics/bts635" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1093/bioinformatics/bts635">https://doi.org/10.1093/bioinformatics/bts635</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1093/bioinformatics/bts635" data-track-item_id="10.1093/bioinformatics/bts635" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1093%2Fbioinformatics%2Fbts635" aria-label="Article reference 27" data-doi="10.1093/bioinformatics/bts635">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23104886" aria-label="PubMed reference 27">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC38XhvV2gsbnF" aria-label="CAS reference 27">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 27" href="http://scholar.google.com/scholar_lookup?&title=STAR%3A%20ultrafast%20universal%20RNA-seq%20aligner&journal=Bioinformatics&doi=10.1093%2Fbioinformatics%2Fbts635&volume=29&pages=15-21&publication_year=2013&author=Dobin%2CA&author=Davis%2CCA&author=Schlesinger%2CF&author=Drenkow%2CJ&author=Zaleski%2CC&author=Jha%2CS&author=Batut%2CP&author=Chaisson%2CM&author=Gingeras%2CTR"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="28."><p class="c-article-references__text" id="ref-CR28">Ehrlich M, Hallmann AL, Reinhardt P, Arauzo-Bravo MJ, Korr S, Ropke A et al (2015) Distinct neurodegenerative changes in an induced pluripotent stem cell model of frontotemporal dementia linked to mutant TAU protein. Stem Cell Reports 5:83–96. <a href="https://doi.org/10.1016/j.stemcr.2015.06.001" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1016/j.stemcr.2015.06.001">https://doi.org/10.1016/j.stemcr.2015.06.001</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.stemcr.2015.06.001" data-track-item_id="10.1016/j.stemcr.2015.06.001" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.stemcr.2015.06.001" aria-label="Article reference 28" data-doi="10.1016/j.stemcr.2015.06.001">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=26143746" aria-label="PubMed reference 28">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4618448" aria-label="PubMed Central reference 28">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC2MXhtFajsL%2FF" aria-label="CAS reference 28">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 28" href="http://scholar.google.com/scholar_lookup?&title=Distinct%20neurodegenerative%20changes%20in%20an%20induced%20pluripotent%20stem%20cell%20model%20of%20frontotemporal%20dementia%20linked%20to%20mutant%20TAU%20protein&journal=Stem%20Cell%20Reports&doi=10.1016%2Fj.stemcr.2015.06.001&volume=5&pages=83-96&publication_year=2015&author=Ehrlich%2CM&author=Hallmann%2CAL&author=Reinhardt%2CP&author=Arauzo-Bravo%2CMJ&author=Korr%2CS&author=Ropke%2CA&author=Psathaki%2COE&author=Ehling%2CP&author=Meuth%2CSG&author=Oblak%2CAL"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="29."><p class="c-article-references__text" id="ref-CR29">Evidente VG, Adler CH, Sabbagh MN, Connor DJ, Hentz JG, Caviness JN et al (2011) Neuropathological findings of PSP in the elderly without clinical PSP: possible incidental PSP? Parkinsonism Relat Disord 17:365–371. <a href="https://doi.org/10.1016/j.parkreldis.2011.02.017" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1016/j.parkreldis.2011.02.017">https://doi.org/10.1016/j.parkreldis.2011.02.017</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.parkreldis.2011.02.017" data-track-item_id="10.1016/j.parkreldis.2011.02.017" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.parkreldis.2011.02.017" aria-label="Article reference 29" data-doi="10.1016/j.parkreldis.2011.02.017">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=21420891" aria-label="PubMed reference 29">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109165" aria-label="PubMed Central reference 29">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 29" href="http://scholar.google.com/scholar_lookup?&title=Neuropathological%20findings%20of%20PSP%20in%20the%20elderly%20without%20clinical%20PSP%3A%20possible%20incidental%20PSP%3F&journal=Parkinsonism%20Relat%20Disord&doi=10.1016%2Fj.parkreldis.2011.02.017&volume=17&pages=365-371&publication_year=2011&author=Evidente%2CVG&author=Adler%2CCH&author=Sabbagh%2CMN&author=Connor%2CDJ&author=Hentz%2CJG&author=Caviness%2CJN&author=Sue%2CLI&author=Beach%2CTG"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="30."><p class="c-article-references__text" id="ref-CR30">Ferrer I, Gomez A, Carmona M, Huesa G, Porta S, Riera-Codina M et al (2011) Neuronal hemoglobin is reduced in Alzheimer’s disease, argyrophilic grain disease, Parkinson’s disease, and dementia with Lewy bodies. J Alzheimers Dis 23:537–550. <a href="https://doi.org/10.3233/JAD-2010-101485" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.3233/JAD-2010-101485">https://doi.org/10.3233/JAD-2010-101485</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.3233/JAD-2010-101485" data-track-item_id="10.3233/JAD-2010-101485" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.3233%2FJAD-2010-101485" aria-label="Article reference 30" data-doi="10.3233/JAD-2010-101485">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=21157025" aria-label="PubMed reference 30">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC3MXhvFersbk%3D" aria-label="CAS reference 30">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 30" href="http://scholar.google.com/scholar_lookup?&title=Neuronal%20hemoglobin%20is%20reduced%20in%20Alzheimer%27s%20disease%2C%20argyrophilic%20grain%20disease%2C%20Parkinson%27s%20disease%2C%20and%20dementia%20with%20Lewy%20bodies&journal=J%20Alzheimers%20Dis&doi=10.3233%2FJAD-2010-101485&volume=23&pages=537-550&publication_year=2011&author=Ferrer%2CI&author=Gomez%2CA&author=Carmona%2CM&author=Huesa%2CG&author=Porta%2CS&author=Riera-Codina%2CM&author=Biagioli%2CM&author=Gustincich%2CS&author=Aso%2CE"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="31."><p class="c-article-references__text" id="ref-CR31">Finak G, McDavid A, Yajima M, Deng J, Gersuk V, Shalek AK et al (2015) MAST: a flexible statistical framework for assessing transcriptional changes and characterizing heterogeneity in single-cell RNA sequencing data. Genome Biol 16:278. <a href="https://doi.org/10.1186/s13059-015-0844-5" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1186/s13059-015-0844-5">https://doi.org/10.1186/s13059-015-0844-5</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/s13059-015-0844-5" data-track-item_id="10.1186/s13059-015-0844-5" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/s13059-015-0844-5" aria-label="Article reference 31" data-doi="10.1186/s13059-015-0844-5">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=26653891" aria-label="PubMed reference 31">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4676162" aria-label="PubMed Central reference 31">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC28XhtFals7nE" aria-label="CAS reference 31">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 31" href="http://scholar.google.com/scholar_lookup?&title=MAST%3A%20a%20flexible%20statistical%20framework%20for%20assessing%20transcriptional%20changes%20and%20characterizing%20heterogeneity%20in%20single-cell%20RNA%20sequencing%20data&journal=Genome%20Biol&doi=10.1186%2Fs13059-015-0844-5&volume=16&publication_year=2015&author=Finak%2CG&author=McDavid%2CA&author=Yajima%2CM&author=Deng%2CJ&author=Gersuk%2CV&author=Shalek%2CAK&author=Slichter%2CCK&author=Miller%2CHW&author=McElrath%2CMJ&author=Prlic%2CM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="32."><p class="c-article-references__text" id="ref-CR32">Foroutan P, Murray ME, Fujioka S, Schweitzer KJ, Dickson DW, Wszolek ZK et al (2013) Progressive supranuclear palsy: high-field-strength MR microscopy in the human substantia nigra and globus pallidus. Radiology 266:280–288. <a href="https://doi.org/10.1148/radiol.12102273" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1148/radiol.12102273">https://doi.org/10.1148/radiol.12102273</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1148/radiol.12102273" data-track-item_id="10.1148/radiol.12102273" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1148%2Fradiol.12102273" aria-label="Article reference 32" data-doi="10.1148/radiol.12102273">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23151826" aria-label="PubMed reference 32">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528969" aria-label="PubMed Central reference 32">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 32" href="http://scholar.google.com/scholar_lookup?&title=Progressive%20supranuclear%20palsy%3A%20high-field-strength%20MR%20microscopy%20in%20the%20human%20substantia%20nigra%20and%20globus%20pallidus&journal=Radiology&doi=10.1148%2Fradiol.12102273&volume=266&pages=280-288&publication_year=2013&author=Foroutan%2CP&author=Murray%2CME&author=Fujioka%2CS&author=Schweitzer%2CKJ&author=Dickson%2CDW&author=Wszolek%2CZK&author=Grant%2CSC"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="33."><p class="c-article-references__text" id="ref-CR33">Forrest SL, Kril JJ, Halliday GM (2019) Cellular and regional vulnerability in frontotemporal tauopathies. Acta Neuropathol 138:705–727. <a href="https://doi.org/10.1007/s00401-019-02035-7" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1007/s00401-019-02035-7">https://doi.org/10.1007/s00401-019-02035-7</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1007/s00401-019-02035-7" data-track-item_id="10.1007/s00401-019-02035-7" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1007/s00401-019-02035-7" aria-label="Article reference 33" data-doi="10.1007/s00401-019-02035-7">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=31203391" aria-label="PubMed reference 33">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 33" href="http://scholar.google.com/scholar_lookup?&title=Cellular%20and%20regional%20vulnerability%20in%20frontotemporal%20tauopathies&journal=Acta%20Neuropathol&doi=10.1007%2Fs00401-019-02035-7&volume=138&pages=705-727&publication_year=2019&author=Forrest%2CSL&author=Kril%2CJJ&author=Halliday%2CGM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="34."><p class="c-article-references__text" id="ref-CR34">Forrest SL, Lee S, Nassir N, Martinez-Valbuena I, Sackmann V, Li J et al (2023) Cell-specific MAPT gene expression is preserved in neuronal and glial tau cytopathologies in progressive supranuclear palsy. Acta Neuropathol 146:395–414. <a href="https://doi.org/10.1007/s00401-023-02604-x" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1007/s00401-023-02604-x">https://doi.org/10.1007/s00401-023-02604-x</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1007/s00401-023-02604-x" data-track-item_id="10.1007/s00401-023-02604-x" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1007/s00401-023-02604-x" aria-label="Article reference 34" data-doi="10.1007/s00401-023-02604-x">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=37354322" aria-label="PubMed reference 34">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10412651" aria-label="PubMed Central reference 34">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3sXhtlGgurfL" aria-label="CAS reference 34">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 34" href="http://scholar.google.com/scholar_lookup?&title=Cell-specific%20MAPT%20gene%20expression%20is%20preserved%20in%20neuronal%20and%20glial%20tau%20cytopathologies%20in%20progressive%20supranuclear%20palsy&journal=Acta%20Neuropathol&doi=10.1007%2Fs00401-023-02604-x&volume=146&pages=395-414&publication_year=2023&author=Forrest%2CSL&author=Lee%2CS&author=Nassir%2CN&author=Martinez-Valbuena%2CI&author=Sackmann%2CV&author=Li%2CJ&author=Ahmed%2CA&author=Tartaglia%2CMC&author=Ittner%2CLM&author=Lang%2CAE"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="35."><p class="c-article-references__text" id="ref-CR35">Foster EM, Dangla-Valls A, Lovestone S, Ribe EM, Buckley NJ (2019) Clusterin in Alzheimer’s disease: mechanisms, genetics, and lessons from other pathologies. Front Neurosci 13:164. <a href="https://doi.org/10.3389/fnins.2019.00164" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.3389/fnins.2019.00164">https://doi.org/10.3389/fnins.2019.00164</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.3389/fnins.2019.00164" data-track-item_id="10.3389/fnins.2019.00164" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.3389%2Ffnins.2019.00164" aria-label="Article reference 35" data-doi="10.3389/fnins.2019.00164">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=30872998" aria-label="PubMed reference 35">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6403191" aria-label="PubMed Central reference 35">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 35" href="http://scholar.google.com/scholar_lookup?&title=Clusterin%20in%20Alzheimer%E2%80%99s%20disease%3A%20mechanisms%2C%20genetics%2C%20and%20lessons%20from%20other%20pathologies&journal=Front%20Neurosci&doi=10.3389%2Ffnins.2019.00164&volume=13&publication_year=2019&author=Foster%2CEM&author=Dangla-Valls%2CA&author=Lovestone%2CS&author=Ribe%2CEM&author=Buckley%2CNJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="36."><p class="c-article-references__text" id="ref-CR36">Fujioka S, Sanchez Contreras MY, Strongosky AJ, Ogaki K, Whaley NR, Tacik PM et al (2015) Three sib-pairs of autopsy-confirmed progressive supranuclear palsy. Parkinsonism Relat Disord 21:101–105. <a href="https://doi.org/10.1016/j.parkreldis.2014.10.028" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1016/j.parkreldis.2014.10.028">https://doi.org/10.1016/j.parkreldis.2014.10.028</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.parkreldis.2014.10.028" data-track-item_id="10.1016/j.parkreldis.2014.10.028" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.parkreldis.2014.10.028" aria-label="Article reference 36" data-doi="10.1016/j.parkreldis.2014.10.028">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=25443551" aria-label="PubMed reference 36">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 36" href="http://scholar.google.com/scholar_lookup?&title=Three%20sib-pairs%20of%20autopsy-confirmed%20progressive%20supranuclear%20palsy&journal=Parkinsonism%20Relat%20Disord&doi=10.1016%2Fj.parkreldis.2014.10.028&volume=21&pages=101-105&publication_year=2015&author=Fujioka%2CS&author=Sanchez%20Contreras%2CMY&author=Strongosky%2CAJ&author=Ogaki%2CK&author=Whaley%2CNR&author=Tacik%2CPM&author=Gerpen%2CJA&author=Uitti%2CRJ&author=Ross%2COA&author=Wszolek%2CZK"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="37."><p class="c-article-references__text" id="ref-CR37">Fujioka S, Van Gerpen JA, Uitti RJ, Dickson DW, Wszolek ZK (2014) Familial progressive supranuclear palsy: a literature review. Neurodegener Dis 13:180–182. <a href="https://doi.org/10.1159/000354975" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1159/000354975">https://doi.org/10.1159/000354975</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1159/000354975" data-track-item_id="10.1159/000354975" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1159%2F000354975" aria-label="Article reference 37" data-doi="10.1159/000354975">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=24080486" aria-label="PubMed reference 37">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC2cXivVCmtLg%3D" aria-label="CAS reference 37">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 37" href="http://scholar.google.com/scholar_lookup?&title=Familial%20progressive%20supranuclear%20palsy%3A%20a%20literature%20review&journal=Neurodegener%20Dis&doi=10.1159%2F000354975&volume=13&pages=180-182&publication_year=2014&author=Fujioka%2CS&author=Gerpen%2CJA&author=Uitti%2CRJ&author=Dickson%2CDW&author=Wszolek%2CZK"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="38."><p class="c-article-references__text" id="ref-CR38">Gami-Patel P, van Dijken I, Meeter LH, Melhem S, Morrema THJ, Scheper W et al (2021) Unfolded protein response activation in C9orf72 frontotemporal dementia is associated with dipeptide pathology and granulovacuolar degeneration in granule cells. Brain Pathol 31:163–173. <a href="https://doi.org/10.1111/bpa.12894" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1111/bpa.12894">https://doi.org/10.1111/bpa.12894</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1111/bpa.12894" data-track-item_id="10.1111/bpa.12894" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1111%2Fbpa.12894" aria-label="Article reference 38" data-doi="10.1111/bpa.12894">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32865835" aria-label="PubMed reference 38">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3MXjtV2gtb8%3D" aria-label="CAS reference 38">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 38" href="http://scholar.google.com/scholar_lookup?&title=Unfolded%20protein%20response%20activation%20in%20C9orf72%20frontotemporal%20dementia%20is%20associated%20with%20dipeptide%20pathology%20and%20granulovacuolar%20degeneration%20in%20granule%20cells&journal=Brain%20Pathol&doi=10.1111%2Fbpa.12894&volume=31&pages=163-173&publication_year=2021&author=Gami-Patel%2CP&author=Dijken%2CI&author=Meeter%2CLH&author=Melhem%2CS&author=Morrema%2CTHJ&author=Scheper%2CW&author=Swieten%2CJC&author=Rozemuller%2CAJM&author=Dijkstra%2CAA&author=Hoozemans%2CJJM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="39."><p class="c-article-references__text" id="ref-CR39">Giannakopoulos P, Kovari E, French LE, Viard I, Hof PR, Bouras C (1998) Possible neuroprotective role of clusterin in Alzheimer’s disease: a quantitative immunocytochemical study. Acta Neuropathol 95:387–394. <a href="https://doi.org/10.1007/s004010050815" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1007/s004010050815">https://doi.org/10.1007/s004010050815</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1007/s004010050815" data-track-item_id="10.1007/s004010050815" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1007/s004010050815" aria-label="Article reference 39" data-doi="10.1007/s004010050815">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=9560017" aria-label="PubMed reference 39">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DyaK1cXislWisL0%3D" aria-label="CAS reference 39">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 39" href="http://scholar.google.com/scholar_lookup?&title=Possible%20neuroprotective%20role%20of%20clusterin%20in%20Alzheimer%27s%20disease%3A%20a%20quantitative%20immunocytochemical%20study&journal=Acta%20Neuropathol&doi=10.1007%2Fs004010050815&volume=95&pages=387-394&publication_year=1998&author=Giannakopoulos%2CP&author=Kovari%2CE&author=French%2CLE&author=Viard%2CI&author=Hof%2CPR&author=Bouras%2CC"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="40."><p class="c-article-references__text" id="ref-CR40">Gong CX, Shaikh S, Wang JZ, Zaidi T, Grundke-Iqbal I, Iqbal K (1995) Phosphatase activity toward abnormally phosphorylated tau: decrease in Alzheimer disease brain. J Neurochem 65:732–738. <a href="https://doi.org/10.1046/j.1471-4159.1995.65020732.x" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1046/j.1471-4159.1995.65020732.x">https://doi.org/10.1046/j.1471-4159.1995.65020732.x</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1046/j.1471-4159.1995.65020732.x" data-track-item_id="10.1046/j.1471-4159.1995.65020732.x" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1046%2Fj.1471-4159.1995.65020732.x" aria-label="Article reference 40" data-doi="10.1046/j.1471-4159.1995.65020732.x">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=7616230" aria-label="PubMed reference 40">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DyaK2MXntFGgsbg%3D" aria-label="CAS reference 40">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 40" href="http://scholar.google.com/scholar_lookup?&title=Phosphatase%20activity%20toward%20abnormally%20phosphorylated%20tau%3A%20decrease%20in%20Alzheimer%20disease%20brain&journal=J%20Neurochem&doi=10.1046%2Fj.1471-4159.1995.65020732.x&volume=65&pages=732-738&publication_year=1995&author=Gong%2CCX&author=Shaikh%2CS&author=Wang%2CJZ&author=Zaidi%2CT&author=Grundke-Iqbal%2CI&author=Iqbal%2CK"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="41."><p class="c-article-references__text" id="ref-CR41">Greene C, Hanley N, Campbell M (2019) Claudin-5: gatekeeper of neurological function. Fluids Barriers CNS 16:3. <a href="https://doi.org/10.1186/s12987-019-0123-z" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1186/s12987-019-0123-z">https://doi.org/10.1186/s12987-019-0123-z</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/s12987-019-0123-z" data-track-item_id="10.1186/s12987-019-0123-z" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/s12987-019-0123-z" aria-label="Article reference 41" data-doi="10.1186/s12987-019-0123-z">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=30691500" aria-label="PubMed reference 41">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350359" aria-label="PubMed Central reference 41">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 41" href="http://scholar.google.com/scholar_lookup?&title=Claudin-5%3A%20gatekeeper%20of%20neurological%20function&journal=Fluids%20Barriers%20CNS&doi=10.1186%2Fs12987-019-0123-z&volume=16&publication_year=2019&author=Greene%2CC&author=Hanley%2CN&author=Campbell%2CM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="42."><p class="c-article-references__text" id="ref-CR42">Grubman A, Chew G, Ouyang JF, Sun G, Choo XY, McLean C et al (2019) A single-cell atlas of entorhinal cortex from individuals with Alzheimer’s disease reveals cell-type-specific gene expression regulation. Nat Neurosci 22:2087–2097. <a href="https://doi.org/10.1038/s41593-019-0539-4" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1038/s41593-019-0539-4">https://doi.org/10.1038/s41593-019-0539-4</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/s41593-019-0539-4" data-track-item_id="10.1038/s41593-019-0539-4" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fs41593-019-0539-4" aria-label="Article reference 42" data-doi="10.1038/s41593-019-0539-4">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=31768052" aria-label="PubMed reference 42">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC1MXit1Ohs7zF" aria-label="CAS reference 42">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 42" href="http://scholar.google.com/scholar_lookup?&title=A%20single-cell%20atlas%20of%20entorhinal%20cortex%20from%20individuals%20with%20Alzheimer%27s%20disease%20reveals%20cell-type-specific%20gene%20expression%20regulation&journal=Nat%20Neurosci&doi=10.1038%2Fs41593-019-0539-4&volume=22&pages=2087-2097&publication_year=2019&author=Grubman%2CA&author=Chew%2CG&author=Ouyang%2CJF&author=Sun%2CG&author=Choo%2CXY&author=McLean%2CC&author=Simmons%2CRK&author=Buckberry%2CS&author=Vargas-Landin%2CDB&author=Poppe%2CD"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="43."><p class="c-article-references__text" id="ref-CR43">Hafemeister C, Satija R (2019) Normalization and variance stabilization of single-cell RNA-seq data using regularized negative binomial regression. Genome Biol 20:296. <a href="https://doi.org/10.1186/s13059-019-1874-1" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1186/s13059-019-1874-1">https://doi.org/10.1186/s13059-019-1874-1</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/s13059-019-1874-1" data-track-item_id="10.1186/s13059-019-1874-1" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/s13059-019-1874-1" aria-label="Article reference 43" data-doi="10.1186/s13059-019-1874-1">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=31870423" aria-label="PubMed reference 43">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927181" aria-label="PubMed Central reference 43">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC1MXisVyht7fF" aria-label="CAS reference 43">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 43" href="http://scholar.google.com/scholar_lookup?&title=Normalization%20and%20variance%20stabilization%20of%20single-cell%20RNA-seq%20data%20using%20regularized%20negative%20binomial%20regression&journal=Genome%20Biol&doi=10.1186%2Fs13059-019-1874-1&volume=20&publication_year=2019&author=Hafemeister%2CC&author=Satija%2CR"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="44."><p class="c-article-references__text" id="ref-CR44">Hafner A, Glavan G, Obermajer N, Zivin M, Schliebs R, Kos J (2013) Neuroprotective role of gamma-enolase in microglia in a mouse model of Alzheimer’s disease is regulated by cathepsin X. Aging Cell 12:604–614. <a href="https://doi.org/10.1111/acel.12093" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1111/acel.12093">https://doi.org/10.1111/acel.12093</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1111/acel.12093" data-track-item_id="10.1111/acel.12093" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1111%2Facel.12093" aria-label="Article reference 44" data-doi="10.1111/acel.12093">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23621429" aria-label="PubMed reference 44">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC3sXhtlCku7nJ" aria-label="CAS reference 44">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 44" href="http://scholar.google.com/scholar_lookup?&title=Neuroprotective%20role%20of%20gamma-enolase%20in%20microglia%20in%20a%20mouse%20model%20of%20Alzheimer%27s%20disease%20is%20regulated%20by%20cathepsin%20X&journal=Aging%20Cell&doi=10.1111%2Facel.12093&volume=12&pages=604-614&publication_year=2013&author=Hafner%2CA&author=Glavan%2CG&author=Obermajer%2CN&author=Zivin%2CM&author=Schliebs%2CR&author=Kos%2CJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="45."><p class="c-article-references__text" id="ref-CR45">Hagestedt T, Lichtenberg B, Wille H, Mandelkow EM, Mandelkow E (1989) Tau protein becomes long and stiff upon phosphorylation: correlation between paracrystalline structure and degree of phosphorylation. J Cell Biol 109:1643–1651. <a href="https://doi.org/10.1083/jcb.109.4.1643" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1083/jcb.109.4.1643">https://doi.org/10.1083/jcb.109.4.1643</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1083/jcb.109.4.1643" data-track-item_id="10.1083/jcb.109.4.1643" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1083%2Fjcb.109.4.1643" aria-label="Article reference 45" data-doi="10.1083/jcb.109.4.1643">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=2507554" aria-label="PubMed reference 45">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DyaL1MXls12ltbs%3D" aria-label="CAS reference 45">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 45" href="http://scholar.google.com/scholar_lookup?&title=Tau%20protein%20becomes%20long%20and%20stiff%20upon%20phosphorylation%3A%20correlation%20between%20paracrystalline%20structure%20and%20degree%20of%20phosphorylation&journal=J%20Cell%20Biol&doi=10.1083%2Fjcb.109.4.1643&volume=109&pages=1643-1651&publication_year=1989&author=Hagestedt%2CT&author=Lichtenberg%2CB&author=Wille%2CH&author=Mandelkow%2CEM&author=Mandelkow%2CE"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="46."><p class="c-article-references__text" id="ref-CR46">Harashima S, Wang Y, Horiuchi T, Seino Y, Inagaki N (2011) Purkinje cell protein 4 positively regulates neurite outgrowth and neurotransmitter release. J Neurosci Res 89:1519–1530. <a href="https://doi.org/10.1002/jnr.22688" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1002/jnr.22688">https://doi.org/10.1002/jnr.22688</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1002/jnr.22688" data-track-item_id="10.1002/jnr.22688" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2Fjnr.22688" aria-label="Article reference 46" data-doi="10.1002/jnr.22688">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=21671256" aria-label="PubMed reference 46">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC3MXpvFajtrk%3D" aria-label="CAS reference 46">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 46" href="http://scholar.google.com/scholar_lookup?&title=Purkinje%20cell%20protein%204%20positively%20regulates%20neurite%20outgrowth%20and%20neurotransmitter%20release&journal=J%20Neurosci%20Res&doi=10.1002%2Fjnr.22688&volume=89&pages=1519-1530&publication_year=2011&author=Harashima%2CS&author=Wang%2CY&author=Horiuchi%2CT&author=Seino%2CY&author=Inagaki%2CN"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="47."><p class="c-article-references__text" id="ref-CR47">Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML et al (2009) Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet 41:1088–1093. <a href="https://doi.org/10.1038/ng.440" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1038/ng.440">https://doi.org/10.1038/ng.440</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/ng.440" data-track-item_id="10.1038/ng.440" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fng.440" aria-label="Article reference 47" data-doi="10.1038/ng.440">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=19734902" aria-label="PubMed reference 47">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2845877" aria-label="PubMed Central reference 47">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD1MXhtV2gsbrM" aria-label="CAS reference 47">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 47" href="http://scholar.google.com/scholar_lookup?&title=Genome-wide%20association%20study%20identifies%20variants%20at%20CLU%20and%20PICALM%20associated%20with%20Alzheimer%27s%20disease&journal=Nat%20Genet&doi=10.1038%2Fng.440&volume=41&pages=1088-1093&publication_year=2009&author=Harold%2CD&author=Abraham%2CR&author=Hollingworth%2CP&author=Sims%2CR&author=Gerrish%2CA&author=Hamshere%2CML&author=Pahwa%2CJS&author=Moskvina%2CV&author=Dowzell%2CK&author=Williams%2CA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="48."><p class="c-article-references__text" id="ref-CR48">Hashimoto Y, Niikura T, Tajima H, Yasukawa T, Sudo H, Ito Y et al (2001) A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer’s disease genes and Abeta. Proc Natl Acad Sci U S A 98:6336–6341. <a href="https://doi.org/10.1073/pnas.101133498" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1073/pnas.101133498">https://doi.org/10.1073/pnas.101133498</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1073/pnas.101133498" data-track-item_id="10.1073/pnas.101133498" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1073%2Fpnas.101133498" aria-label="Article reference 48" data-doi="10.1073/pnas.101133498">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=11371646" aria-label="PubMed reference 48">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC33469" aria-label="PubMed Central reference 48">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD3MXktVWksbk%3D" aria-label="CAS reference 48">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 48" href="http://scholar.google.com/scholar_lookup?&title=A%20rescue%20factor%20abolishing%20neuronal%20cell%20death%20by%20a%20wide%20spectrum%20of%20familial%20Alzheimer%27s%20disease%20genes%20and%20Abeta&journal=Proc%20Natl%20Acad%20Sci%20U%20S%20A&doi=10.1073%2Fpnas.101133498&volume=98&pages=6336-6341&publication_year=2001&author=Hashimoto%2CY&author=Niikura%2CT&author=Tajima%2CH&author=Yasukawa%2CT&author=Sudo%2CH&author=Ito%2CY&author=Kita%2CY&author=Kawasumi%2CM&author=Kouyama%2CK&author=Doyu%2CM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="49."><p class="c-article-references__text" id="ref-CR49">Hauw JJ, Daniel SE, Dickson D, Horoupian DS, Jellinger K, Lantos PL et al (1994) Preliminary NINDS neuropathologic criteria for Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy). Neurology 44:2015–2019. <a href="https://doi.org/10.1212/wnl.44.11.2015" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1212/wnl.44.11.2015">https://doi.org/10.1212/wnl.44.11.2015</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1212/wnl.44.11.2015" data-track-item_id="10.1212/wnl.44.11.2015" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1212%2Fwnl.44.11.2015" aria-label="Article reference 49" data-doi="10.1212/wnl.44.11.2015">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=7969952" aria-label="PubMed reference 49">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:STN:280:DyaK2M%2FlvF2rtg%3D%3D" aria-label="CAS reference 49">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 49" href="http://scholar.google.com/scholar_lookup?&title=Preliminary%20NINDS%20neuropathologic%20criteria%20for%20Steele-Richardson-Olszewski%20syndrome%20%28progressive%20supranuclear%20palsy%29&journal=Neurology&doi=10.1212%2Fwnl.44.11.2015&volume=44&pages=2015-2019&publication_year=1994&author=Hauw%2CJJ&author=Daniel%2CSE&author=Dickson%2CD&author=Horoupian%2CDS&author=Jellinger%2CK&author=Lantos%2CPL&author=McKee%2CA&author=Tabaton%2CM&author=Litvan%2CI"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="50."><p class="c-article-references__text" id="ref-CR50">Hauw JJ, Verny M, Delaere P, Cervera P, He Y, Duyckaerts C (1990) Constant neurofibrillary changes in the neocortex in progressive supranuclear palsy. Basic differences with Alzheimer’s disease and aging. Neurosci Lett 119:182–186. <a href="https://doi.org/10.1016/0304-3940(90)90829-x" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1016/0304-3940(90)90829-x">https://doi.org/10.1016/0304-3940(90)90829-x</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/0304-3940(90)90829-x" data-track-item_id="10.1016/0304-3940(90)90829-x" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2F0304-3940%2890%2990829-x" aria-label="Article reference 50" data-doi="10.1016/0304-3940(90)90829-x">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=1704110" aria-label="PubMed reference 50">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:STN:280:DyaK3M7isFKqsw%3D%3D" aria-label="CAS reference 50">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 50" href="http://scholar.google.com/scholar_lookup?&title=Constant%20neurofibrillary%20changes%20in%20the%20neocortex%20in%20progressive%20supranuclear%20palsy.%20Basic%20differences%20with%20Alzheimer%27s%20disease%20and%20aging&journal=Neurosci%20Lett&doi=10.1016%2F0304-3940%2890%2990829-x&volume=119&pages=182-186&publication_year=1990&author=Hauw%2CJJ&author=Verny%2CM&author=Delaere%2CP&author=Cervera%2CP&author=He%2CY&author=Duyckaerts%2CC"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="51."><p class="c-article-references__text" id="ref-CR51">Hetz C (2012) The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol 13:89–102. <a href="https://doi.org/10.1038/nrm3270" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1038/nrm3270">https://doi.org/10.1038/nrm3270</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/nrm3270" data-track-item_id="10.1038/nrm3270" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fnrm3270" aria-label="Article reference 51" data-doi="10.1038/nrm3270">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=22251901" aria-label="PubMed reference 51">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC38XnvVeltQ%3D%3D" aria-label="CAS reference 51">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 51" href="http://scholar.google.com/scholar_lookup?&title=The%20unfolded%20protein%20response%3A%20controlling%20cell%20fate%20decisions%20under%20ER%20stress%20and%20beyond&journal=Nat%20Rev%20Mol%20Cell%20Biol&doi=10.1038%2Fnrm3270&volume=13&pages=89-102&publication_year=2012&author=Hetz%2CC"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="52."><p class="c-article-references__text" id="ref-CR52">Hoffman GE, Schadt EE (2016) variancePartition: interpreting drivers of variation in complex gene expression studies. BMC Bioinformatics 17:483. <a href="https://doi.org/10.1186/s12859-016-1323-z" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1186/s12859-016-1323-z">https://doi.org/10.1186/s12859-016-1323-z</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/s12859-016-1323-z" data-track-item_id="10.1186/s12859-016-1323-z" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/s12859-016-1323-z" aria-label="Article reference 52" data-doi="10.1186/s12859-016-1323-z">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=27884101" aria-label="PubMed reference 52">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5123296" aria-label="PubMed Central reference 52">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 52" href="http://scholar.google.com/scholar_lookup?&title=variancePartition%3A%20interpreting%20drivers%20of%20variation%20in%20complex%20gene%20expression%20studies&journal=BMC%20Bioinformatics&doi=10.1186%2Fs12859-016-1323-z&volume=17&publication_year=2016&author=Hoffman%2CGE&author=Schadt%2CEE"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="53."><p class="c-article-references__text" id="ref-CR53">Hoglinger GU, Melhem NM, Dickson DW, Sleiman PM, Wang LS, Klei L et al (2011) Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet 43:699–705. <a href="https://doi.org/10.1038/ng.859" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1038/ng.859">https://doi.org/10.1038/ng.859</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/ng.859" data-track-item_id="10.1038/ng.859" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fng.859" aria-label="Article reference 53" data-doi="10.1038/ng.859">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=21685912" aria-label="PubMed reference 53">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3125476" aria-label="PubMed Central reference 53">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC3MXnslSls7s%3D" aria-label="CAS reference 53">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 53" href="http://scholar.google.com/scholar_lookup?&title=Identification%20of%20common%20variants%20influencing%20risk%20of%20the%20tauopathy%20progressive%20supranuclear%20palsy&journal=Nat%20Genet&doi=10.1038%2Fng.859&volume=43&pages=699-705&publication_year=2011&author=Hoglinger%2CGU&author=Melhem%2CNM&author=Dickson%2CDW&author=Sleiman%2CPM&author=Wang%2CLS&author=Klei%2CL&author=Rademakers%2CR&author=Silva%2CR&author=Litvan%2CI&author=Riley%2CDE"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="54."><p class="c-article-references__text" id="ref-CR54">Hoozemans JJ, van Haastert ES, Nijholt DA, Rozemuller AJ, Eikelenboom P, Scheper W (2009) The unfolded protein response is activated in pretangle neurons in Alzheimer’s disease hippocampus. Am J Pathol 174:1241–1251. <a href="https://doi.org/10.2353/ajpath.2009.080814" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.2353/ajpath.2009.080814">https://doi.org/10.2353/ajpath.2009.080814</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.2353/ajpath.2009.080814" data-track-item_id="10.2353/ajpath.2009.080814" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.2353%2Fajpath.2009.080814" aria-label="Article reference 54" data-doi="10.2353/ajpath.2009.080814">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=19264902" aria-label="PubMed reference 54">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2671357" aria-label="PubMed Central reference 54">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD1MXksVOkt74%3D" aria-label="CAS reference 54">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 54" href="http://scholar.google.com/scholar_lookup?&title=The%20unfolded%20protein%20response%20is%20activated%20in%20pretangle%20neurons%20in%20Alzheimer%27s%20disease%20hippocampus&journal=Am%20J%20Pathol&doi=10.2353%2Fajpath.2009.080814&volume=174&pages=1241-1251&publication_year=2009&author=Hoozemans%2CJJ&author=Haastert%2CES&author=Nijholt%2CDA&author=Rozemuller%2CAJ&author=Eikelenboom%2CP&author=Scheper%2CW"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="55."><p class="c-article-references__text" id="ref-CR55">Hoozemans JJ, van Haastert ES, Nijholt DA, Rozemuller AJ, Scheper W (2012) Activation of the unfolded protein response is an early event in Alzheimer’s and Parkinson’s disease. Neurodegener Dis 10:212–215. <a href="https://doi.org/10.1159/000334536" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1159/000334536">https://doi.org/10.1159/000334536</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1159/000334536" data-track-item_id="10.1159/000334536" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1159%2F000334536" aria-label="Article reference 55" data-doi="10.1159/000334536">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=22302012" aria-label="PubMed reference 55">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC38XlvVOmur4%3D" aria-label="CAS reference 55">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 55" href="http://scholar.google.com/scholar_lookup?&title=Activation%20of%20the%20unfolded%20protein%20response%20is%20an%20early%20event%20in%20Alzheimer%27s%20and%20Parkinson%27s%20disease&journal=Neurodegener%20Dis&doi=10.1159%2F000334536&volume=10&pages=212-215&publication_year=2012&author=Hoozemans%2CJJ&author=Haastert%2CES&author=Nijholt%2CDA&author=Rozemuller%2CAJ&author=Scheper%2CW"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="56."><p class="c-article-references__text" id="ref-CR56">Institute B (2018) Picard tools - by broad institute <a href="https://broadinstitute.github.io/picard/" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="https://broadinstitute.github.io/picard/">https://broadinstitute.github.io/picard/</a></p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="57."><p class="c-article-references__text" id="ref-CR57">Kamath T, Abdulraouf A, Burris SJ, Langlieb J, Gazestani V, Nadaf NM et al (2022) Single-cell genomic profiling of human dopamine neurons identifies a population that selectively degenerates in Parkinson’s disease. Nat Neurosci 25:588–595. <a href="https://doi.org/10.1038/s41593-022-01061-1" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1038/s41593-022-01061-1">https://doi.org/10.1038/s41593-022-01061-1</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/s41593-022-01061-1" data-track-item_id="10.1038/s41593-022-01061-1" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fs41593-022-01061-1" aria-label="Article reference 57" data-doi="10.1038/s41593-022-01061-1">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=35513515" aria-label="PubMed reference 57">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9076534" aria-label="PubMed Central reference 57">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB38Xht1agtL%2FN" aria-label="CAS reference 57">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 57" href="http://scholar.google.com/scholar_lookup?&title=Single-cell%20genomic%20profiling%20of%20human%20dopamine%20neurons%20identifies%20a%20population%20that%20selectively%20degenerates%20in%20Parkinson%27s%20disease&journal=Nat%20Neurosci&doi=10.1038%2Fs41593-022-01061-1&volume=25&pages=588-595&publication_year=2022&author=Kamath%2CT&author=Abdulraouf%2CA&author=Burris%2CSJ&author=Langlieb%2CJ&author=Gazestani%2CV&author=Nadaf%2CNM&author=Balderrama%2CK&author=Vanderburg%2CC&author=Macosko%2CEZ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="58."><p class="c-article-references__text" id="ref-CR58">Kim SH, Nairn AC, Cairns N, Lubec G (2001) Decreased levels of ARPP-19 and PKA in brains of down syndrome and Alzheimer’s disease. J Neural Transm Suppl. <a href="https://doi.org/10.1007/978-3-7091-6262-0_21" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1007/978-3-7091-6262-0_21">https://doi.org/10.1007/978-3-7091-6262-0_21</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1007/978-3-7091-6262-0_21" data-track-item_id="10.1007/978-3-7091-6262-0_21" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1007/978-3-7091-6262-0_21" aria-label="Article reference 58" data-doi="10.1007/978-3-7091-6262-0_21">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=11771750" aria-label="PubMed reference 58">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 58" href="http://scholar.google.com/scholar_lookup?&title=Decreased%20levels%20of%20ARPP-19%20and%20PKA%20in%20brains%20of%20down%20syndrome%20and%20Alzheimer%27s%20disease&journal=J%20Neural%20Transm%20Suppl&doi=10.1007%2F978-3-7091-6262-0_21&publication_year=2001&author=Kim%2CSH&author=Nairn%2CAC&author=Cairns%2CN&author=Lubec%2CG"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="59."><p class="c-article-references__text" id="ref-CR59">Kiselev VY, Andrews TS, Hemberg M (2019) Challenges in unsupervised clustering of single-cell RNA-seq data. Nat Rev Genet 20:273–282. <a href="https://doi.org/10.1038/s41576-018-0088-9" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1038/s41576-018-0088-9">https://doi.org/10.1038/s41576-018-0088-9</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/s41576-018-0088-9" data-track-item_id="10.1038/s41576-018-0088-9" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fs41576-018-0088-9" aria-label="Article reference 59" data-doi="10.1038/s41576-018-0088-9">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=30617341" aria-label="PubMed reference 59">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC1MXlvFSit7s%3D" aria-label="CAS reference 59">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 59" href="http://scholar.google.com/scholar_lookup?&title=Challenges%20in%20unsupervised%20clustering%20of%20single-cell%20RNA-seq%20data&journal=Nat%20Rev%20Genet&doi=10.1038%2Fs41576-018-0088-9&volume=20&pages=273-282&publication_year=2019&author=Kiselev%2CVY&author=Andrews%2CTS&author=Hemberg%2CM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="60."><p class="c-article-references__text" id="ref-CR60">Koh JY, Lee SJ (2020) Metallothionein-3 as a multifunctional player in the control of cellular processes and diseases. Mol Brain 13:116. <a href="https://doi.org/10.1186/s13041-020-00654-w" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1186/s13041-020-00654-w">https://doi.org/10.1186/s13041-020-00654-w</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/s13041-020-00654-w" data-track-item_id="10.1186/s13041-020-00654-w" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/s13041-020-00654-w" aria-label="Article reference 60" data-doi="10.1186/s13041-020-00654-w">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32843100" aria-label="PubMed reference 60">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448430" aria-label="PubMed Central reference 60">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXhs1ygsLnL" aria-label="CAS reference 60">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 60" href="http://scholar.google.com/scholar_lookup?&title=Metallothionein-3%20as%20a%20multifunctional%20player%20in%20the%20control%20of%20cellular%20processes%20and%20diseases&journal=Mol%20Brain&doi=10.1186%2Fs13041-020-00654-w&volume=13&publication_year=2020&author=Koh%2CJY&author=Lee%2CSJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="61."><p class="c-article-references__text" id="ref-CR61">Korsunsky I, Millard N, Fan J, Slowikowski K, Zhang F, Wei K et al (2019) Fast, sensitive and accurate integration of single-cell data with Harmony. Nat Methods 16:1289–1296. <a href="https://doi.org/10.1038/s41592-019-0619-0" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1038/s41592-019-0619-0">https://doi.org/10.1038/s41592-019-0619-0</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/s41592-019-0619-0" data-track-item_id="10.1038/s41592-019-0619-0" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fs41592-019-0619-0" aria-label="Article reference 61" data-doi="10.1038/s41592-019-0619-0">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=31740819" aria-label="PubMed reference 61">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884693" aria-label="PubMed Central reference 61">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC1MXitFOqsr7N" aria-label="CAS reference 61">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 61" href="http://scholar.google.com/scholar_lookup?&title=Fast%2C%20sensitive%20and%20accurate%20integration%20of%20single-cell%20data%20with%20Harmony&journal=Nat%20Methods&doi=10.1038%2Fs41592-019-0619-0&volume=16&pages=1289-1296&publication_year=2019&author=Korsunsky%2CI&author=Millard%2CN&author=Fan%2CJ&author=Slowikowski%2CK&author=Zhang%2CF&author=Wei%2CK&author=Baglaenko%2CY&author=Brenner%2CM&author=Loh%2CPR&author=Raychaudhuri%2CS"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="62."><p class="c-article-references__text" id="ref-CR62">Kovacs GG, Lukic MJ, Irwin DJ, Arzberger T, Respondek G, Lee EB et al (2020) Distribution patterns of tau pathology in progressive supranuclear palsy. Acta Neuropathol 140:99–119. <a href="https://doi.org/10.1007/s00401-020-02158-2" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1007/s00401-020-02158-2">https://doi.org/10.1007/s00401-020-02158-2</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1007/s00401-020-02158-2" data-track-item_id="10.1007/s00401-020-02158-2" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1007/s00401-020-02158-2" aria-label="Article reference 62" data-doi="10.1007/s00401-020-02158-2">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32383020" aria-label="PubMed reference 62">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360645" aria-label="PubMed Central reference 62">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 62" href="http://scholar.google.com/scholar_lookup?&title=Distribution%20patterns%20of%20tau%20pathology%20in%20progressive%20supranuclear%20palsy&journal=Acta%20Neuropathol&doi=10.1007%2Fs00401-020-02158-2&volume=140&pages=99-119&publication_year=2020&author=Kovacs%2CGG&author=Lukic%2CMJ&author=Irwin%2CDJ&author=Arzberger%2CT&author=Respondek%2CG&author=Lee%2CEB&author=Coughlin%2CD&author=Giese%2CA&author=Grossman%2CM&author=Kurz%2CC"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="63."><p class="c-article-references__text" id="ref-CR63">Kramer A, Green J, Pollard J Jr, Tugendreich S (2014) Causal analysis approaches in ingenuity pathway analysis. Bioinformatics 30:523–530. <a href="https://doi.org/10.1093/bioinformatics/btt703" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1093/bioinformatics/btt703">https://doi.org/10.1093/bioinformatics/btt703</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1093/bioinformatics/btt703" data-track-item_id="10.1093/bioinformatics/btt703" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1093%2Fbioinformatics%2Fbtt703" aria-label="Article reference 63" data-doi="10.1093/bioinformatics/btt703">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=24336805" aria-label="PubMed reference 63">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC2cXjtVCls78%3D" aria-label="CAS reference 63">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 63" href="http://scholar.google.com/scholar_lookup?&title=Causal%20analysis%20approaches%20in%20ingenuity%20pathway%20analysis&journal=Bioinformatics&doi=10.1093%2Fbioinformatics%2Fbtt703&volume=30&pages=523-530&publication_year=2014&author=Kramer%2CA&author=Green%2CJ&author=Pollard%2CJ&author=Tugendreich%2CS"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="64."><p class="c-article-references__text" id="ref-CR64">Kwon J, Kim J, Kim KI (2023) Crosstalk between endoplasmic reticulum stress response and autophagy in human diseases. Anim Cells Syst (Seoul) 27:29–37. <a href="https://doi.org/10.1080/19768354.2023.2181217" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1080/19768354.2023.2181217">https://doi.org/10.1080/19768354.2023.2181217</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1080/19768354.2023.2181217" data-track-item_id="10.1080/19768354.2023.2181217" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1080%2F19768354.2023.2181217" aria-label="Article reference 64" data-doi="10.1080/19768354.2023.2181217">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=36860271" aria-label="PubMed reference 64">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 64" href="http://scholar.google.com/scholar_lookup?&title=Crosstalk%20between%20endoplasmic%20reticulum%20stress%20response%20and%20autophagy%20in%20human%20diseases&journal=Anim%20Cells%20Syst%20%28Seoul%29&doi=10.1080%2F19768354.2023.2181217&volume=27&pages=29-37&publication_year=2023&author=Kwon%2CJ&author=Kim%2CJ&author=Kim%2CKI"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="65."><p class="c-article-references__text" id="ref-CR65">LaFerla FM (2002) Calcium dyshomeostasis and intracellular signalling in Alzheimer’s disease. Nat Rev Neurosci 3:862–872. <a href="https://doi.org/10.1038/nrn960" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1038/nrn960">https://doi.org/10.1038/nrn960</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/nrn960" data-track-item_id="10.1038/nrn960" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fnrn960" aria-label="Article reference 65" data-doi="10.1038/nrn960">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=12415294" aria-label="PubMed reference 65">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD38Xotleqtr8%3D" aria-label="CAS reference 65">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 65" href="http://scholar.google.com/scholar_lookup?&title=Calcium%20dyshomeostasis%20and%20intracellular%20signalling%20in%20Alzheimer%27s%20disease&journal=Nat%20Rev%20Neurosci&doi=10.1038%2Fnrn960&volume=3&pages=862-872&publication_year=2002&author=LaFerla%2CFM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="66."><p class="c-article-references__text" id="ref-CR66">Lai S, Wang Y, Li T, Dong Y, Lin Y, Wang L et al (2022) N6-methyladenosine-mediated CELF2 regulates CD44 alternative splicing affecting tumorigenesis via ERAD pathway in pancreatic cancer. Cell Biosci 12:125. <a href="https://doi.org/10.1186/s13578-022-00844-0" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1186/s13578-022-00844-0">https://doi.org/10.1186/s13578-022-00844-0</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/s13578-022-00844-0" data-track-item_id="10.1186/s13578-022-00844-0" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/s13578-022-00844-0" aria-label="Article reference 66" data-doi="10.1186/s13578-022-00844-0">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=35941702" aria-label="PubMed reference 66">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9361702" aria-label="PubMed Central reference 66">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB38XitlOmtr%2FM" aria-label="CAS reference 66">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 66" href="http://scholar.google.com/scholar_lookup?&title=N6-methyladenosine-mediated%20CELF2%20regulates%20CD44%20alternative%20splicing%20affecting%20tumorigenesis%20via%20ERAD%20pathway%20in%20pancreatic%20cancer&journal=Cell%20Biosci&doi=10.1186%2Fs13578-022-00844-0&volume=12&publication_year=2022&author=Lai%2CS&author=Wang%2CY&author=Li%2CT&author=Dong%2CY&author=Lin%2CY&author=Wang%2CL&author=Weng%2CS&author=Zhang%2CX&author=Lin%2CC"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="67."><p class="c-article-references__text" id="ref-CR67">Law CW, Chen Y, Shi W, Smyth GK (2014) voom: precision weights unlock linear model analysis tools for RNA-seq read counts. Genome Biol 15:R29. <a href="https://doi.org/10.1186/gb-2014-15-2-r29" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1186/gb-2014-15-2-r29">https://doi.org/10.1186/gb-2014-15-2-r29</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/gb-2014-15-2-r29" data-track-item_id="10.1186/gb-2014-15-2-r29" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/gb-2014-15-2-r29" aria-label="Article reference 67" data-doi="10.1186/gb-2014-15-2-r29">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=24485249" aria-label="PubMed reference 67">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4053721" aria-label="PubMed Central reference 67">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC2MXjsVeltbw%3D" aria-label="CAS reference 67">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 67" href="http://scholar.google.com/scholar_lookup?&title=voom%3A%20precision%20weights%20unlock%20linear%20model%20analysis%20tools%20for%20RNA-seq%20read%20counts&journal=Genome%20Biol&doi=10.1186%2Fgb-2014-15-2-r29&volume=15&publication_year=2014&author=Law%2CCW&author=Chen%2CY&author=Shi%2CW&author=Smyth%2CGK"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="68."><p class="c-article-references__text" id="ref-CR68">Lee S, Martinez-Valbuena I, de Andrea CE, Villalba-Esparza M, Ilaalagan S, Couto B et al (2023) Cell-specific dysregulation of iron and oxygen homeostasis as a novel pathophysiology in PSP. Ann Neurol 93:431–445. <a href="https://doi.org/10.1002/ana.26540" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1002/ana.26540">https://doi.org/10.1002/ana.26540</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1002/ana.26540" data-track-item_id="10.1002/ana.26540" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2Fana.26540" aria-label="Article reference 68" data-doi="10.1002/ana.26540">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=36309960" aria-label="PubMed reference 68">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB38XjtVKqu7rN" aria-label="CAS reference 68">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 68" href="http://scholar.google.com/scholar_lookup?&title=Cell-specific%20dysregulation%20of%20iron%20and%20oxygen%20homeostasis%20as%20a%20novel%20pathophysiology%20in%20PSP&journal=Ann%20Neurol&doi=10.1002%2Fana.26540&volume=93&pages=431-445&publication_year=2023&author=Lee%2CS&author=Martinez-Valbuena%2CI&author=Andrea%2CCE&author=Villalba-Esparza%2CM&author=Ilaalagan%2CS&author=Couto%2CB&author=Visanji%2CNP&author=Lang%2CAE&author=Kovacs%2CGG"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="69."><p class="c-article-references__text" id="ref-CR69">Leng K, Li E, Eser R, Piergies A, Sit R, Tan M et al (2021) Molecular characterization of selectively vulnerable neurons in Alzheimer’s disease. Nat Neurosci 24:276–287. <a href="https://doi.org/10.1038/s41593-020-00764-7" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1038/s41593-020-00764-7">https://doi.org/10.1038/s41593-020-00764-7</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/s41593-020-00764-7" data-track-item_id="10.1038/s41593-020-00764-7" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fs41593-020-00764-7" aria-label="Article reference 69" data-doi="10.1038/s41593-020-00764-7">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33432193" aria-label="PubMed reference 69">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854528" aria-label="PubMed Central reference 69">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3MXhtVGku7c%3D" aria-label="CAS reference 69">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 69" href="http://scholar.google.com/scholar_lookup?&title=Molecular%20characterization%20of%20selectively%20vulnerable%20neurons%20in%20Alzheimer%27s%20disease&journal=Nat%20Neurosci&doi=10.1038%2Fs41593-020-00764-7&volume=24&pages=276-287&publication_year=2021&author=Leng%2CK&author=Li%2CE&author=Eser%2CR&author=Piergies%2CA&author=Sit%2CR&author=Tan%2CM&author=Neff%2CN&author=Li%2CSH&author=Rodriguez%2CRD&author=Suemoto%2CCK"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="70."><p class="c-article-references__text" id="ref-CR70">Li B, Dewey CN (2011) RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. Bmc Bioinform 12:323. <a href="https://doi.org/10.1186/1471-2105-12-323" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1186/1471-2105-12-323">https://doi.org/10.1186/1471-2105-12-323</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/1471-2105-12-323" data-track-item_id="10.1186/1471-2105-12-323" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/1471-2105-12-323" aria-label="Article reference 70" data-doi="10.1186/1471-2105-12-323">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC3MXhtFajtLvM" aria-label="CAS reference 70">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 70" href="http://scholar.google.com/scholar_lookup?&title=RSEM%3A%20accurate%20transcript%20quantification%20from%20RNA-Seq%20data%20with%20or%20without%20a%20reference%20genome&journal=Bmc%20Bioinform&doi=10.1186%2F1471-2105-12-323&volume=12&publication_year=2011&author=Li%2CB&author=Dewey%2CCN"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="71."><p class="c-article-references__text" id="ref-CR71">Liao Y, Smyth GK, Shi W (2014) featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 30:923–930. <a href="https://doi.org/10.1093/bioinformatics/btt656" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1093/bioinformatics/btt656">https://doi.org/10.1093/bioinformatics/btt656</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1093/bioinformatics/btt656" data-track-item_id="10.1093/bioinformatics/btt656" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1093%2Fbioinformatics%2Fbtt656" aria-label="Article reference 71" data-doi="10.1093/bioinformatics/btt656">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=24227677" aria-label="PubMed reference 71">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC2cXltFGqu7c%3D" aria-label="CAS reference 71">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 71" href="http://scholar.google.com/scholar_lookup?&title=featureCounts%3A%20an%20efficient%20general%20purpose%20program%20for%20assigning%20sequence%20reads%20to%20genomic%20features&journal=Bioinformatics&doi=10.1093%2Fbioinformatics%2Fbtt656&volume=30&pages=923-930&publication_year=2014&author=Liao%2CY&author=Smyth%2CGK&author=Shi%2CW"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="72."><p class="c-article-references__text" id="ref-CR72">Liberzon A, Birger C, Thorvaldsdottir H, Ghandi M, Mesirov JP, Tamayo P (2015) The molecular signatures database (MSigDB) hallmark gene set collection. Cell Syst 1:417–425. <a href="https://doi.org/10.1016/j.cels.2015.12.004" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1016/j.cels.2015.12.004">https://doi.org/10.1016/j.cels.2015.12.004</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.cels.2015.12.004" data-track-item_id="10.1016/j.cels.2015.12.004" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.cels.2015.12.004" aria-label="Article reference 72" data-doi="10.1016/j.cels.2015.12.004">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=26771021" aria-label="PubMed reference 72">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707969" aria-label="PubMed Central reference 72">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC2sXhtFaltLc%3D" aria-label="CAS reference 72">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 72" href="http://scholar.google.com/scholar_lookup?&title=The%20molecular%20signatures%20database%20%28MSigDB%29%20hallmark%20gene%20set%20collection&journal=Cell%20Syst&doi=10.1016%2Fj.cels.2015.12.004&volume=1&pages=417-425&publication_year=2015&author=Liberzon%2CA&author=Birger%2CC&author=Thorvaldsdottir%2CH&author=Ghandi%2CM&author=Mesirov%2CJP&author=Tamayo%2CP"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="73."><p class="c-article-references__text" id="ref-CR73">Litvan I, Hauw JJ, Bartko JJ, Lantos PL, Daniel SE, Horoupian DS et al (1996) Validity and reliability of the preliminary NINDS neuropathologic criteria for progressive supranuclear palsy and related disorders. J Neuropathol Exp Neurol 55:97–105. <a href="https://doi.org/10.1097/00005072-199601000-00010" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1097/00005072-199601000-00010">https://doi.org/10.1097/00005072-199601000-00010</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1097/00005072-199601000-00010" data-track-item_id="10.1097/00005072-199601000-00010" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1097%2F00005072-199601000-00010" aria-label="Article reference 73" data-doi="10.1097/00005072-199601000-00010">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=8558176" aria-label="PubMed reference 73">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:STN:280:DyaK287js1Wlsw%3D%3D" aria-label="CAS reference 73">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 73" href="http://scholar.google.com/scholar_lookup?&title=Validity%20and%20reliability%20of%20the%20preliminary%20NINDS%20neuropathologic%20criteria%20for%20progressive%20supranuclear%20palsy%20and%20related%20disorders&journal=J%20Neuropathol%20Exp%20Neurol&doi=10.1097%2F00005072-199601000-00010&volume=55&pages=97-105&publication_year=1996&author=Litvan%2CI&author=Hauw%2CJJ&author=Bartko%2CJJ&author=Lantos%2CPL&author=Daniel%2CSE&author=Horoupian%2CDS&author=McKee%2CA&author=Dickson%2CD&author=Bancher%2CC&author=Tabaton%2CM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="74."><p class="c-article-references__text" id="ref-CR74">Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G (2013) Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 9:106–118. <a href="https://doi.org/10.1038/nrneurol.2012.263" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1038/nrneurol.2012.263">https://doi.org/10.1038/nrneurol.2012.263</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/nrneurol.2012.263" data-track-item_id="10.1038/nrneurol.2012.263" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fnrneurol.2012.263" aria-label="Article reference 74" data-doi="10.1038/nrneurol.2012.263">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=23296339" aria-label="PubMed reference 74">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3726719" aria-label="PubMed Central reference 74">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC3sXis1Ggs7Y%3D" aria-label="CAS reference 74">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 74" href="http://scholar.google.com/scholar_lookup?&title=Apolipoprotein%20E%20and%20Alzheimer%20disease%3A%20risk%2C%20mechanisms%20and%20therapy&journal=Nat%20Rev%20Neurol&doi=10.1038%2Fnrneurol.2012.263&volume=9&pages=106-118&publication_year=2013&author=Liu%2CCC&author=Liu%2CCC&author=Kanekiyo%2CT&author=Xu%2CH&author=Bu%2CG"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="75."><p class="c-article-references__text" id="ref-CR75">Lu PD, Jousse C, Marciniak SJ, Zhang Y, Novoa I, Scheuner D et al (2004) Cytoprotection by pre-emptive conditional phosphorylation of translation initiation factor 2. EMBO J 23:169–179. <a href="https://doi.org/10.1038/sj.emboj.7600030" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1038/sj.emboj.7600030">https://doi.org/10.1038/sj.emboj.7600030</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/sj.emboj.7600030" data-track-item_id="10.1038/sj.emboj.7600030" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fsj.emboj.7600030" aria-label="Article reference 75" data-doi="10.1038/sj.emboj.7600030">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=14713949" aria-label="PubMed reference 75">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1271668" aria-label="PubMed Central reference 75">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD2cXhtVeqtbg%3D" aria-label="CAS reference 75">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 75" href="http://scholar.google.com/scholar_lookup?&title=Cytoprotection%20by%20pre-emptive%20conditional%20phosphorylation%20of%20translation%20initiation%20factor%202&journal=EMBO%20J&doi=10.1038%2Fsj.emboj.7600030&volume=23&pages=169-179&publication_year=2004&author=Lu%2CPD&author=Jousse%2CC&author=Marciniak%2CSJ&author=Zhang%2CY&author=Novoa%2CI&author=Scheuner%2CD&author=Kaufman%2CRJ&author=Ron%2CD&author=Harding%2CHP"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="76."><p class="c-article-references__text" id="ref-CR76">Lyons S, Trepel D, Lynch T, Walsh R, O’Dowd S (2023) The prevalence and incidence of progressive supranuclear palsy and corticobasal syndrome: a systematic review and meta-analysis. J Neurol 270:4451–4465. <a href="https://doi.org/10.1007/s00415-023-11791-2" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1007/s00415-023-11791-2">https://doi.org/10.1007/s00415-023-11791-2</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1007/s00415-023-11791-2" data-track-item_id="10.1007/s00415-023-11791-2" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1007/s00415-023-11791-2" aria-label="Article reference 76" data-doi="10.1007/s00415-023-11791-2">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=37289323" aria-label="PubMed reference 76">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10421779" aria-label="PubMed Central reference 76">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 76" href="http://scholar.google.com/scholar_lookup?&title=The%20prevalence%20and%20incidence%20of%20progressive%20supranuclear%20palsy%20and%20corticobasal%20syndrome%3A%20a%20systematic%20review%20and%20meta-analysis&journal=J%20Neurol&doi=10.1007%2Fs00415-023-11791-2&volume=270&pages=4451-4465&publication_year=2023&author=Lyons%2CS&author=Trepel%2CD&author=Lynch%2CT&author=Walsh%2CR&author=O%27Dowd%2CS"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="77."><p class="c-article-references__text" id="ref-CR77">Mathys H, Davila-Velderrain J, Peng Z, Gao F, Mohammadi S, Young JZ et al (2019) Single-cell transcriptomic analysis of Alzheimer’s disease. Nature 570:332–337. <a href="https://doi.org/10.1038/s41586-019-1195-2" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1038/s41586-019-1195-2">https://doi.org/10.1038/s41586-019-1195-2</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/s41586-019-1195-2" data-track-item_id="10.1038/s41586-019-1195-2" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fs41586-019-1195-2" aria-label="Article reference 77" data-doi="10.1038/s41586-019-1195-2">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=31042697" aria-label="PubMed reference 77">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865822" aria-label="PubMed Central reference 77">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC1MXhtVajsrjI" aria-label="CAS reference 77">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 77" href="http://scholar.google.com/scholar_lookup?&title=Single-cell%20transcriptomic%20analysis%20of%20Alzheimer%27s%20disease&journal=Nature&doi=10.1038%2Fs41586-019-1195-2&volume=570&pages=332-337&publication_year=2019&author=Mathys%2CH&author=Davila-Velderrain%2CJ&author=Peng%2CZ&author=Gao%2CF&author=Mohammadi%2CS&author=Young%2CJZ&author=Menon%2CM&author=He%2CL&author=Abdurrob%2CF&author=Jiang%2CX"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="78."><p class="c-article-references__text" id="ref-CR78">May PC, Johnson SA, Poirier J, Lampert-Etchells M, Finch CE (1989) Altered gene expression in Alzheimer’s disease brain tissue. Can J Neurol Sci 16:473–476. <a href="https://doi.org/10.1017/s0317167100029796" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1017/s0317167100029796">https://doi.org/10.1017/s0317167100029796</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1017/s0317167100029796" data-track-item_id="10.1017/s0317167100029796" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1017%2Fs0317167100029796" aria-label="Article reference 78" data-doi="10.1017/s0317167100029796">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=2680007" aria-label="PubMed reference 78">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:STN:280:DyaK3c%2FivF2nsA%3D%3D" aria-label="CAS reference 78">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 78" href="http://scholar.google.com/scholar_lookup?&title=Altered%20gene%20expression%20in%20Alzheimer%27s%20disease%20brain%20tissue&journal=Can%20J%20Neurol%20Sci&doi=10.1017%2Fs0317167100029796&volume=16&pages=473-476&publication_year=1989&author=May%2CPC&author=Johnson%2CSA&author=Poirier%2CJ&author=Lampert-Etchells%2CM&author=Finch%2CCE"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="79."><p class="c-article-references__text" id="ref-CR79">McCarthy DJ, Smyth GK (2009) Testing significance relative to a fold-change threshold is a TREAT. Bioinformatics 25:765–771. <a href="https://doi.org/10.1093/bioinformatics/btp053" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1093/bioinformatics/btp053">https://doi.org/10.1093/bioinformatics/btp053</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1093/bioinformatics/btp053" data-track-item_id="10.1093/bioinformatics/btp053" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1093%2Fbioinformatics%2Fbtp053" aria-label="Article reference 79" data-doi="10.1093/bioinformatics/btp053">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=19176553" aria-label="PubMed reference 79">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2654802" aria-label="PubMed Central reference 79">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD1MXjt1ektL8%3D" aria-label="CAS reference 79">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 79" href="http://scholar.google.com/scholar_lookup?&title=Testing%20significance%20relative%20to%20a%20fold-change%20threshold%20is%20a%20TREAT&journal=Bioinformatics&doi=10.1093%2Fbioinformatics%2Fbtp053&volume=25&pages=765-771&publication_year=2009&author=McCarthy%2CDJ&author=Smyth%2CGK"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="80."><p class="c-article-references__text" id="ref-CR80">McGinnis CS, Murrow LM, Gartner ZJ (2019) DoubletFinder: doublet detection in single-cell RNA sequencing data using artificial nearest neighbors. Cell Syst 8(329–337):e324. <a href="https://doi.org/10.1016/j.cels.2019.03.003" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1016/j.cels.2019.03.003">https://doi.org/10.1016/j.cels.2019.03.003</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.cels.2019.03.003" data-track-item_id="10.1016/j.cels.2019.03.003" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.cels.2019.03.003" aria-label="Article reference 80" data-doi="10.1016/j.cels.2019.03.003">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC1MXosVyhtbk%3D" aria-label="CAS reference 80">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 80" href="http://scholar.google.com/scholar_lookup?&title=DoubletFinder%3A%20doublet%20detection%20in%20single-cell%20RNA%20sequencing%20data%20using%20artificial%20nearest%20neighbors&journal=Cell%20Syst&doi=10.1016%2Fj.cels.2019.03.003&volume=8&issue=329%E2%80%93337&publication_year=2019&author=McGinnis%2CCS&author=Murrow%2CLM&author=Gartner%2CZJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="81."><p class="c-article-references__text" id="ref-CR81">McKenzie AT, Wang M, Hauberg ME, Fullard JF, Kozlenkov A, Keenan A et al (2018) Brain cell type specific gene expression and co-expression network architectures. Sci Rep 8:8868. <a href="https://doi.org/10.1038/s41598-018-27293-5" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1038/s41598-018-27293-5">https://doi.org/10.1038/s41598-018-27293-5</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/s41598-018-27293-5" data-track-item_id="10.1038/s41598-018-27293-5" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fs41598-018-27293-5" aria-label="Article reference 81" data-doi="10.1038/s41598-018-27293-5">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=29892006" aria-label="PubMed reference 81">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995803" aria-label="PubMed Central reference 81">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC1cXhsl2jur7J" aria-label="CAS reference 81">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 81" href="http://scholar.google.com/scholar_lookup?&title=Brain%20cell%20type%20specific%20gene%20expression%20and%20co-expression%20network%20architectures&journal=Sci%20Rep&doi=10.1038%2Fs41598-018-27293-5&volume=8&publication_year=2018&author=McKenzie%2CAT&author=Wang%2CM&author=Hauberg%2CME&author=Fullard%2CJF&author=Kozlenkov%2CA&author=Keenan%2CA&author=Hurd%2CYL&author=Dracheva%2CS&author=Casaccia%2CP&author=Roussos%2CP"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="82."><p class="c-article-references__text" id="ref-CR82">Miller JA, Guillozet-Bongaarts A, Gibbons LE, Postupna N, Renz A, Beller AE et al (2017) Neuropathological and transcriptomic characteristics of the aged brain. Elife. <a href="https://doi.org/10.7554/eLife.31126" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.7554/eLife.31126">https://doi.org/10.7554/eLife.31126</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.7554/eLife.31126" data-track-item_id="10.7554/eLife.31126" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.7554%2FeLife.31126" aria-label="Article reference 82" data-doi="10.7554/eLife.31126">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=29120328" aria-label="PubMed reference 82">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5679757" aria-label="PubMed Central reference 82">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 82" href="http://scholar.google.com/scholar_lookup?&title=Neuropathological%20and%20transcriptomic%20characteristics%20of%20the%20aged%20brain&journal=Elife&doi=10.7554%2FeLife.31126&publication_year=2017&author=Miller%2CJA&author=Guillozet-Bongaarts%2CA&author=Gibbons%2CLE&author=Postupna%2CN&author=Renz%2CA&author=Beller%2CAE&author=Sunkin%2CSM&author=Ng%2CL&author=Rose%2CSE&author=Smith%2CKA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="83."><p class="c-article-references__text" id="ref-CR83">Min Y, Wang X, Is O, Patel TA, Gao J, Reddy JS et al (2023) Cross species systems biology discovers glial DDR2, STOM, and KANK2 as therapeutic targets in progressive supranuclear palsy. Nat Commun 14:6801. <a href="https://doi.org/10.1038/s41467-023-42626-3" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1038/s41467-023-42626-3">https://doi.org/10.1038/s41467-023-42626-3</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/s41467-023-42626-3" data-track-item_id="10.1038/s41467-023-42626-3" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fs41467-023-42626-3" aria-label="Article reference 83" data-doi="10.1038/s41467-023-42626-3">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=37919278" aria-label="PubMed reference 83">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10622416" aria-label="PubMed Central reference 83">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3sXit1yrtrzN" aria-label="CAS reference 83">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 83" href="http://scholar.google.com/scholar_lookup?&title=Cross%20species%20systems%20biology%20discovers%20glial%20DDR2%2C%20STOM%2C%20and%20KANK2%20as%20therapeutic%20targets%20in%20progressive%20supranuclear%20palsy&journal=Nat%20Commun&doi=10.1038%2Fs41467-023-42626-3&volume=14&publication_year=2023&author=Min%2CY&author=Wang%2CX&author=Is%2CO&author=Patel%2CTA&author=Gao%2CJ&author=Reddy%2CJS&author=Quicksall%2CZS&author=Nguyen%2CT&author=Lin%2CS&author=Tutor-New%2CFQ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="84."><p class="c-article-references__text" id="ref-CR84">Nijholt DA, van Haastert ES, Rozemuller AJ, Scheper W, Hoozemans JJ (2012) The unfolded protein response is associated with early tau pathology in the hippocampus of tauopathies. J Pathol 226:693–702. <a href="https://doi.org/10.1002/path.3969" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1002/path.3969">https://doi.org/10.1002/path.3969</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1002/path.3969" data-track-item_id="10.1002/path.3969" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2Fpath.3969" aria-label="Article reference 84" data-doi="10.1002/path.3969">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=22102449" aria-label="PubMed reference 84">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC38XjsVWht7w%3D" aria-label="CAS reference 84">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 84" href="http://scholar.google.com/scholar_lookup?&title=The%20unfolded%20protein%20response%20is%20associated%20with%20early%20tau%20pathology%20in%20the%20hippocampus%20of%20tauopathies&journal=J%20Pathol&doi=10.1002%2Fpath.3969&volume=226&pages=693-702&publication_year=2012&author=Nijholt%2CDA&author=Haastert%2CES&author=Rozemuller%2CAJ&author=Scheper%2CW&author=Hoozemans%2CJJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="85."><p class="c-article-references__text" id="ref-CR85">Otero-Garcia M, Mahajani SU, Wakhloo D, Tang W, Xue YQ, Morabito S et al (2022) Molecular signatures underlying neurofibrillary tangle susceptibility in Alzheimer’s disease. Neuron 110(2929–2948):e2928. <a href="https://doi.org/10.1016/j.neuron.2022.06.021" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1016/j.neuron.2022.06.021">https://doi.org/10.1016/j.neuron.2022.06.021</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.neuron.2022.06.021" data-track-item_id="10.1016/j.neuron.2022.06.021" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.neuron.2022.06.021" aria-label="Article reference 85" data-doi="10.1016/j.neuron.2022.06.021">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB38XhvFejsr%2FE" aria-label="CAS reference 85">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 85" href="http://scholar.google.com/scholar_lookup?&title=Molecular%20signatures%20underlying%20neurofibrillary%20tangle%20susceptibility%20in%20Alzheimer%27s%20disease&journal=Neuron&doi=10.1016%2Fj.neuron.2022.06.021&volume=110&issue=2929%E2%80%932948&publication_year=2022&author=Otero-Garcia%2CM&author=Mahajani%2CSU&author=Wakhloo%2CD&author=Tang%2CW&author=Xue%2CYQ&author=Morabito%2CS&author=Pan%2CJ&author=Oberhauser%2CJ&author=Madira%2CAE&author=Shakouri%2CT"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="86."><p class="c-article-references__text" id="ref-CR86">Pakos-Zebrucka K, Koryga I, Mnich K, Ljujic M, Samali A, Gorman AM (2016) The integrated stress response. EMBO Rep 17:1374–1395. <a href="https://doi.org/10.15252/embr.201642195" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.15252/embr.201642195">https://doi.org/10.15252/embr.201642195</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.15252/embr.201642195" data-track-item_id="10.15252/embr.201642195" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.15252%2Fembr.201642195" aria-label="Article reference 86" data-doi="10.15252/embr.201642195">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=27629041" aria-label="PubMed reference 86">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5048378" aria-label="PubMed Central reference 86">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC28XhsFSjtL3I" aria-label="CAS reference 86">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 86" href="http://scholar.google.com/scholar_lookup?&title=The%20integrated%20stress%20response&journal=EMBO%20Rep&doi=10.15252%2Fembr.201642195&volume=17&pages=1374-1395&publication_year=2016&author=Pakos-Zebrucka%2CK&author=Koryga%2CI&author=Mnich%2CK&author=Ljujic%2CM&author=Samali%2CA&author=Gorman%2CAM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="87."><p class="c-article-references__text" id="ref-CR87">Park G, Xu K, Chea L, Kim K, Safarta L, Song KH et al (2023) Neurodegeneration risk factor, EIF2AK3 (PERK), influences tau protein aggregation. J Biol Chem 299:102821. <a href="https://doi.org/10.1016/j.jbc.2022.102821" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1016/j.jbc.2022.102821">https://doi.org/10.1016/j.jbc.2022.102821</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.jbc.2022.102821" data-track-item_id="10.1016/j.jbc.2022.102821" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.jbc.2022.102821" aria-label="Article reference 87" data-doi="10.1016/j.jbc.2022.102821">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=36563857" aria-label="PubMed reference 87">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3sXht1ylt70%3D" aria-label="CAS reference 87">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 87" href="http://scholar.google.com/scholar_lookup?&title=Neurodegeneration%20risk%20factor%2C%20EIF2AK3%20%28PERK%29%2C%20influences%20tau%20protein%20aggregation&journal=J%20Biol%20Chem&doi=10.1016%2Fj.jbc.2022.102821&volume=299&publication_year=2023&author=Park%2CG&author=Xu%2CK&author=Chea%2CL&author=Kim%2CK&author=Safarta%2CL&author=Song%2CKH&author=Wu%2CJ&author=Park%2CS&author=Min%2CH&author=Hiramatsu%2CN"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="88."><p class="c-article-references__text" id="ref-CR88">Pellegrini L, Bonfio C, Chadwick J, Begum F, Skehel M, Lancaster MA (2020) Human CNS barrier-forming organoids with cerebrospinal fluid production. Science. <a href="https://doi.org/10.1126/science.aaz5626" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1126/science.aaz5626">https://doi.org/10.1126/science.aaz5626</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1126/science.aaz5626" data-track-item_id="10.1126/science.aaz5626" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1126%2Fscience.aaz5626" aria-label="Article reference 88" data-doi="10.1126/science.aaz5626">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=32788292" aria-label="PubMed reference 88">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665312" aria-label="PubMed Central reference 88">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 88" href="http://scholar.google.com/scholar_lookup?&title=Human%20CNS%20barrier-forming%20organoids%20with%20cerebrospinal%20fluid%20production&journal=Science&doi=10.1126%2Fscience.aaz5626&publication_year=2020&author=Pellegrini%2CL&author=Bonfio%2CC&author=Chadwick%2CJ&author=Begum%2CF&author=Skehel%2CM&author=Lancaster%2CMA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="89."><p class="c-article-references__text" id="ref-CR89">Pitera AP, Asuni AA, O’Connor V, Deinhardt K (2019) Pathogenic tau does not drive activation of the unfolded protein response. J Biol Chem 294:9679–9688. <a href="https://doi.org/10.1074/jbc.RA119.008263" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1074/jbc.RA119.008263">https://doi.org/10.1074/jbc.RA119.008263</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1074/jbc.RA119.008263" data-track-item_id="10.1074/jbc.RA119.008263" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1074%2Fjbc.RA119.008263" aria-label="Article reference 89" data-doi="10.1074/jbc.RA119.008263">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=31053641" aria-label="PubMed reference 89">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597832" aria-label="PubMed Central reference 89">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB38XisVOmsLbJ" aria-label="CAS reference 89">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 89" href="http://scholar.google.com/scholar_lookup?&title=Pathogenic%20tau%20does%20not%20drive%20activation%20of%20the%20unfolded%20protein%20response&journal=J%20Biol%20Chem&doi=10.1074%2Fjbc.RA119.008263&volume=294&pages=9679-9688&publication_year=2019&author=Pitera%2CAP&author=Asuni%2CAA&author=O%27Connor%2CV&author=Deinhardt%2CK"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="90."><p class="c-article-references__text" id="ref-CR90">Pitera AP, Hartnell IJ, Scullard L, Williamson KL, Boche D, O’Connor V et al (2021) Molecular investigation of the unfolded protein response in select human tauopathies. J Alzheimers Dis Rep 5:855–869. <a href="https://doi.org/10.3233/ADR-210050" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.3233/ADR-210050">https://doi.org/10.3233/ADR-210050</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.3233/ADR-210050" data-track-item_id="10.3233/ADR-210050" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.3233%2FADR-210050" aria-label="Article reference 90" data-doi="10.3233/ADR-210050">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=35088035" aria-label="PubMed reference 90">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8764631" aria-label="PubMed Central reference 90">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 90" href="http://scholar.google.com/scholar_lookup?&title=Molecular%20investigation%20of%20the%20unfolded%20protein%20response%20in%20select%20human%20tauopathies&journal=J%20Alzheimers%20Dis%20Rep&doi=10.3233%2FADR-210050&volume=5&pages=855-869&publication_year=2021&author=Pitera%2CAP&author=Hartnell%2CIJ&author=Scullard%2CL&author=Williamson%2CKL&author=Boche%2CD&author=O%27Connor%2CV&author=Deinhardt%2CK"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="91."><p class="c-article-references__text" id="ref-CR91">Qi Y, Li Y, Zhang Y, Zhang L, Wang Z, Zhang X et al (2015) IFI6 inhibits apoptosis via mitochondrial-dependent pathway in dengue virus 2 infected vascular endothelial cells. PLoS ONE 10:e0132743. <a href="https://doi.org/10.1371/journal.pone.0132743" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1371/journal.pone.0132743">https://doi.org/10.1371/journal.pone.0132743</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1371/journal.pone.0132743" data-track-item_id="10.1371/journal.pone.0132743" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1371%2Fjournal.pone.0132743" aria-label="Article reference 91" data-doi="10.1371/journal.pone.0132743">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=26244642" aria-label="PubMed reference 91">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526556" aria-label="PubMed Central reference 91">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC2MXhvV2jtbrE" aria-label="CAS reference 91">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 91" href="http://scholar.google.com/scholar_lookup?&title=IFI6%20inhibits%20apoptosis%20via%20mitochondrial-dependent%20pathway%20in%20dengue%20virus%202%20infected%20vascular%20endothelial%20cells&journal=PLoS%20ONE&doi=10.1371%2Fjournal.pone.0132743&volume=10&publication_year=2015&author=Qi%2CY&author=Li%2CY&author=Zhang%2CY&author=Zhang%2CL&author=Wang%2CZ&author=Zhang%2CX&author=Gui%2CL&author=Huang%2CJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="92."><p class="c-article-references__text" id="ref-CR92">Qian W, Yin X, Hu W, Shi J, Gu J, Grundke-Iqbal I et al (2011) Activation of protein phosphatase 2B and hyperphosphorylation of Tau in Alzheimer’s disease. J Alzheimers Dis 23:617–627. <a href="https://doi.org/10.3233/JAD-2010-100987" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.3233/JAD-2010-100987">https://doi.org/10.3233/JAD-2010-100987</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.3233/JAD-2010-100987" data-track-item_id="10.3233/JAD-2010-100987" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.3233%2FJAD-2010-100987" aria-label="Article reference 92" data-doi="10.3233/JAD-2010-100987">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=21157033" aria-label="PubMed reference 92">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3377165" aria-label="PubMed Central reference 92">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC3MXlvVeltbc%3D" aria-label="CAS reference 92">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 92" href="http://scholar.google.com/scholar_lookup?&title=Activation%20of%20protein%20phosphatase%202B%20and%20hyperphosphorylation%20of%20Tau%20in%20Alzheimer%27s%20disease&journal=J%20Alzheimers%20Dis&doi=10.3233%2FJAD-2010-100987&volume=23&pages=617-627&publication_year=2011&author=Qian%2CW&author=Yin%2CX&author=Hu%2CW&author=Shi%2CJ&author=Gu%2CJ&author=Grundke-Iqbal%2CI&author=Iqbal%2CK&author=Gong%2CCX&author=Liu%2CF"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="93."><p class="c-article-references__text" id="ref-CR93">Quintana C, Bellefqih S, Laval JY, Guerquin-Kern JL, Wu TD, Avila J et al (2006) Study of the localization of iron, ferritin, and hemosiderin in Alzheimer’s disease hippocampus by analytical microscopy at the subcellular level. J Struct Biol 153:42–54. <a href="https://doi.org/10.1016/j.jsb.2005.11.001" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1016/j.jsb.2005.11.001">https://doi.org/10.1016/j.jsb.2005.11.001</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.jsb.2005.11.001" data-track-item_id="10.1016/j.jsb.2005.11.001" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.jsb.2005.11.001" aria-label="Article reference 93" data-doi="10.1016/j.jsb.2005.11.001">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=16364657" aria-label="PubMed reference 93">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD28XhvFygtA%3D%3D" aria-label="CAS reference 93">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 93" href="http://scholar.google.com/scholar_lookup?&title=Study%20of%20the%20localization%20of%20iron%2C%20ferritin%2C%20and%20hemosiderin%20in%20Alzheimer%27s%20disease%20hippocampus%20by%20analytical%20microscopy%20at%20the%20subcellular%20level&journal=J%20Struct%20Biol&doi=10.1016%2Fj.jsb.2005.11.001&volume=153&pages=42-54&publication_year=2006&author=Quintana%2CC&author=Bellefqih%2CS&author=Laval%2CJY&author=Guerquin-Kern%2CJL&author=Wu%2CTD&author=Avila%2CJ&author=Ferrer%2CI&author=Arranz%2CR&author=Patino%2CC"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="94."><p class="c-article-references__text" id="ref-CR94">Rahman A, Grundke-Iqbal I, Iqbal K (2006) PP2B isolated from human brain preferentially dephosphorylates Ser-262 and Ser-396 of the Alzheimer disease abnormally hyperphosphorylated tau. J Neural Transm (Vienna) 113:219–230. <a href="https://doi.org/10.1007/s00702-005-0313-5" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1007/s00702-005-0313-5">https://doi.org/10.1007/s00702-005-0313-5</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1007/s00702-005-0313-5" data-track-item_id="10.1007/s00702-005-0313-5" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1007/s00702-005-0313-5" aria-label="Article reference 94" data-doi="10.1007/s00702-005-0313-5">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=15959850" aria-label="PubMed reference 94">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD28XlsFyqsw%3D%3D" aria-label="CAS reference 94">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 94" href="http://scholar.google.com/scholar_lookup?&title=PP2B%20isolated%20from%20human%20brain%20preferentially%20dephosphorylates%20Ser-262%20and%20Ser-396%20of%20the%20Alzheimer%20disease%20abnormally%20hyperphosphorylated%20tau&journal=J%20Neural%20Transm%20%28Vienna%29&doi=10.1007%2Fs00702-005-0313-5&volume=113&pages=219-230&publication_year=2006&author=Rahman%2CA&author=Grundke-Iqbal%2CI&author=Iqbal%2CK"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="95."><p class="c-article-references__text" id="ref-CR95">Raulin AC, Doss SV, Trottier ZA, Ikezu TC, Bu G, Liu CC (2022) ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies. Mol Neurodegener 17:72. <a href="https://doi.org/10.1186/s13024-022-00574-4" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1186/s13024-022-00574-4">https://doi.org/10.1186/s13024-022-00574-4</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/s13024-022-00574-4" data-track-item_id="10.1186/s13024-022-00574-4" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/s13024-022-00574-4" aria-label="Article reference 95" data-doi="10.1186/s13024-022-00574-4">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=36348357" aria-label="PubMed reference 95">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9644639" aria-label="PubMed Central reference 95">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB38XivVChsr%2FM" aria-label="CAS reference 95">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 95" href="http://scholar.google.com/scholar_lookup?&title=ApoE%20in%20Alzheimer%27s%20disease%3A%20pathophysiology%20and%20therapeutic%20strategies&journal=Mol%20Neurodegener&doi=10.1186%2Fs13024-022-00574-4&volume=17&publication_year=2022&author=Raulin%2CAC&author=Doss%2CSV&author=Trottier%2CZA&author=Ikezu%2CTC&author=Bu%2CG&author=Liu%2CCC"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="96."><p class="c-article-references__text" id="ref-CR96">Relaix F, Wei X, Li W, Pan J, Lin Y, Bowtell DD et al (2000) Pw1/Peg3 is a potential cell death mediator and cooperates with Siah1a in p53-mediated apoptosis. Proc Natl Acad Sci U S A 97:2105–2110. <a href="https://doi.org/10.1073/pnas.040378897" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1073/pnas.040378897">https://doi.org/10.1073/pnas.040378897</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1073/pnas.040378897" data-track-item_id="10.1073/pnas.040378897" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1073%2Fpnas.040378897" aria-label="Article reference 96" data-doi="10.1073/pnas.040378897">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=10681424" aria-label="PubMed reference 96">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC15761" aria-label="PubMed Central reference 96">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD3cXhslKhsbY%3D" aria-label="CAS reference 96">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 96" href="http://scholar.google.com/scholar_lookup?&title=Pw1%2FPeg3%20is%20a%20potential%20cell%20death%20mediator%20and%20cooperates%20with%20Siah1a%20in%20p53-mediated%20apoptosis&journal=Proc%20Natl%20Acad%20Sci%20U%20S%20A&doi=10.1073%2Fpnas.040378897&volume=97&pages=2105-2110&publication_year=2000&author=Relaix%2CF&author=Wei%2CX&author=Li%2CW&author=Pan%2CJ&author=Lin%2CY&author=Bowtell%2CDD&author=Sassoon%2CDA&author=Wu%2CX"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="97."><p class="c-article-references__text" id="ref-CR97">Ren H, Zhai W, Lu X, Wang G (2021) The cross-links of endoplasmic reticulum stress, autophagy, and neurodegeneration in Parkinson’s disease. Front Aging Neurosci 13:691881. <a href="https://doi.org/10.3389/fnagi.2021.691881" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.3389/fnagi.2021.691881">https://doi.org/10.3389/fnagi.2021.691881</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.3389/fnagi.2021.691881" data-track-item_id="10.3389/fnagi.2021.691881" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.3389%2Ffnagi.2021.691881" aria-label="Article reference 97" data-doi="10.3389/fnagi.2021.691881">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=34168552" aria-label="PubMed reference 97">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218021" aria-label="PubMed Central reference 97">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3MXisVKrtbzO" aria-label="CAS reference 97">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 97" href="http://scholar.google.com/scholar_lookup?&title=The%20cross-links%20of%20endoplasmic%20reticulum%20stress%2C%20autophagy%2C%20and%20neurodegeneration%20in%20Parkinson%E2%80%99s%20disease&journal=Front%20Aging%20Neurosci&doi=10.3389%2Ffnagi.2021.691881&volume=13&publication_year=2021&author=Ren%2CH&author=Zhai%2CW&author=Lu%2CX&author=Wang%2CG"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="98."><p class="c-article-references__text" id="ref-CR98">Ressler HW, Humphrey J, Vialle RA, Babrowicz B, Kandoi S, Raj T et al (2024) MAPT haplotype-associated transcriptomic changes in progressive supranuclear palsy. Acta Neuropathol Commun 12:135. <a href="https://doi.org/10.1186/s40478-024-01839-3" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1186/s40478-024-01839-3">https://doi.org/10.1186/s40478-024-01839-3</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/s40478-024-01839-3" data-track-item_id="10.1186/s40478-024-01839-3" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/s40478-024-01839-3" aria-label="Article reference 98" data-doi="10.1186/s40478-024-01839-3">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=39154163" aria-label="PubMed reference 98">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11330133" aria-label="PubMed Central reference 98">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB2cXhvVGlu7vM" aria-label="CAS reference 98">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 98" href="http://scholar.google.com/scholar_lookup?&title=MAPT%20haplotype-associated%20transcriptomic%20changes%20in%20progressive%20supranuclear%20palsy&journal=Acta%20Neuropathol%20Commun&doi=10.1186%2Fs40478-024-01839-3&volume=12&publication_year=2024&author=Ressler%2CHW&author=Humphrey%2CJ&author=Vialle%2CRA&author=Babrowicz%2CB&author=Kandoi%2CS&author=Raj%2CT&author=Dickson%2CDW&author=Ertekin-Taner%2CN&author=Crary%2CJF&author=Farrell%2CK"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="99."><p class="c-article-references__text" id="ref-CR99">Rickner HD, Jiang L, Hong R, O’Neill NK, Mojica CA, Snyder BJ et al (2022) Single cell transcriptomic profiling of a neuron-astrocyte assembloid tauopathy model. Nat Commun 13:6275. <a href="https://doi.org/10.1038/s41467-022-34005-1" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1038/s41467-022-34005-1">https://doi.org/10.1038/s41467-022-34005-1</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/s41467-022-34005-1" data-track-item_id="10.1038/s41467-022-34005-1" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fs41467-022-34005-1" aria-label="Article reference 99" data-doi="10.1038/s41467-022-34005-1">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=36271092" aria-label="PubMed reference 99">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9587045" aria-label="PubMed Central reference 99">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB38XislWiurbL" aria-label="CAS reference 99">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 99" href="http://scholar.google.com/scholar_lookup?&title=Single%20cell%20transcriptomic%20profiling%20of%20a%20neuron-astrocyte%20assembloid%20tauopathy%20model&journal=Nat%20Commun&doi=10.1038%2Fs41467-022-34005-1&volume=13&publication_year=2022&author=Rickner%2CHD&author=Jiang%2CL&author=Hong%2CR&author=O%27Neill%2CNK&author=Mojica%2CCA&author=Snyder%2CBJ&author=Zhang%2CL&author=Shaw%2CD&author=Medalla%2CM&author=Wolozin%2CB"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="100."><p class="c-article-references__text" id="ref-CR100">Rodriguez RD, Grinberg LT (2015) Argyrophilic grain disease: an underestimated tauopathy. Dement Neuropsychol 9:2–8. <a href="https://doi.org/10.1590/S1980-57642015DN91000002" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1590/S1980-57642015DN91000002">https://doi.org/10.1590/S1980-57642015DN91000002</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1590/S1980-57642015DN91000002" data-track-item_id="10.1590/S1980-57642015DN91000002" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1590%2FS1980-57642015DN91000002" aria-label="Article reference 100" data-doi="10.1590/S1980-57642015DN91000002">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=29213935" aria-label="PubMed reference 100">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618985" aria-label="PubMed Central reference 100">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 100" href="http://scholar.google.com/scholar_lookup?&title=Argyrophilic%20grain%20disease%3A%20an%20underestimated%20tauopathy&journal=Dement%20Neuropsychol&doi=10.1590%2FS1980-57642015DN91000002&volume=9&pages=2-8&publication_year=2015&author=Rodriguez%2CRD&author=Grinberg%2CLT"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="101."><p class="c-article-references__text" id="ref-CR101">Roemer SF, Grinberg LT, Crary JF, Seeley WW, McKee AC, Kovacs GG et al (2022) Rainwater charitable foundation criteria for the neuropathologic diagnosis of progressive supranuclear palsy. Acta Neuropathol 144:603–614. <a href="https://doi.org/10.1007/s00401-022-02479-4" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1007/s00401-022-02479-4">https://doi.org/10.1007/s00401-022-02479-4</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1007/s00401-022-02479-4" data-track-item_id="10.1007/s00401-022-02479-4" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1007/s00401-022-02479-4" aria-label="Article reference 101" data-doi="10.1007/s00401-022-02479-4">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=35947184" aria-label="PubMed reference 101">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9468104" aria-label="PubMed Central reference 101">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB38Xit1GrurrI" aria-label="CAS reference 101">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 101" href="http://scholar.google.com/scholar_lookup?&title=Rainwater%20charitable%20foundation%20criteria%20for%20the%20neuropathologic%20diagnosis%20of%20progressive%20supranuclear%20palsy&journal=Acta%20Neuropathol&doi=10.1007%2Fs00401-022-02479-4&volume=144&pages=603-614&publication_year=2022&author=Roemer%2CSF&author=Grinberg%2CLT&author=Crary%2CJF&author=Seeley%2CWW&author=McKee%2CAC&author=Kovacs%2CGG&author=Beach%2CTG&author=Duyckaerts%2CC&author=Ferrer%2CIA&author=Gelpi%2CE"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="102."><p class="c-article-references__text" id="ref-CR102">Rojo A, Pernaute RS, Fontan A, Ruiz PG, Honnorat J, Lynch T et al (1999) Clinical genetics of familial progressive supranuclear palsy. Brain 122(Pt 7):1233–1245. <a href="https://doi.org/10.1093/brain/122.7.1233" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1093/brain/122.7.1233">https://doi.org/10.1093/brain/122.7.1233</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1093/brain/122.7.1233" data-track-item_id="10.1093/brain/122.7.1233" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1093%2Fbrain%2F122.7.1233" aria-label="Article reference 102" data-doi="10.1093/brain/122.7.1233">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=10388790" aria-label="PubMed reference 102">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 102" href="http://scholar.google.com/scholar_lookup?&title=Clinical%20genetics%20of%20familial%20progressive%20supranuclear%20palsy&journal=Brain&doi=10.1093%2Fbrain%2F122.7.1233&volume=122&issue=Pt%207&pages=1233-1245&publication_year=1999&author=Rojo%2CA&author=Pernaute%2CRS&author=Fontan%2CA&author=Ruiz%2CPG&author=Honnorat%2CJ&author=Lynch%2CT&author=Chin%2CS&author=Gonzalo%2CI&author=Rabano%2CA&author=Martinez%2CA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="103."><p class="c-article-references__text" id="ref-CR103">Sakry D, Yigit H, Dimou L, Trotter J (2015) Oligodendrocyte precursor cells synthesize neuromodulatory factors. PLoS ONE 10:e0127222. <a href="https://doi.org/10.1371/journal.pone.0127222" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1371/journal.pone.0127222">https://doi.org/10.1371/journal.pone.0127222</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1371/journal.pone.0127222" data-track-item_id="10.1371/journal.pone.0127222" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1371%2Fjournal.pone.0127222" aria-label="Article reference 103" data-doi="10.1371/journal.pone.0127222">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=25966014" aria-label="PubMed reference 103">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4429067" aria-label="PubMed Central reference 103">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC2MXhvVCmsbjI" aria-label="CAS reference 103">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 103" href="http://scholar.google.com/scholar_lookup?&title=Oligodendrocyte%20precursor%20cells%20synthesize%20neuromodulatory%20factors&journal=PLoS%20ONE&doi=10.1371%2Fjournal.pone.0127222&volume=10&publication_year=2015&author=Sakry%2CD&author=Yigit%2CH&author=Dimou%2CL&author=Trotter%2CJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="104."><p class="c-article-references__text" id="ref-CR104">Sanchez-Contreras MY, Kouri N, Cook CN, Serie DJ, Heckman MG, Finch NA et al (2018) Replication of progressive supranuclear palsy genome-wide association study identifies SLCO1A2 and DUSP10 as new susceptibility loci. Mol Neurodegener 13:37. <a href="https://doi.org/10.1186/s13024-018-0267-3" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1186/s13024-018-0267-3">https://doi.org/10.1186/s13024-018-0267-3</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/s13024-018-0267-3" data-track-item_id="10.1186/s13024-018-0267-3" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/s13024-018-0267-3" aria-label="Article reference 104" data-doi="10.1186/s13024-018-0267-3">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=29986742" aria-label="PubMed reference 104">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6038352" aria-label="PubMed Central reference 104">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC1MXjt1Oiu7Y%3D" aria-label="CAS reference 104">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 104" href="http://scholar.google.com/scholar_lookup?&title=Replication%20of%20progressive%20supranuclear%20palsy%20genome-wide%20association%20study%20identifies%20SLCO1A2%20and%20DUSP10%20as%20new%20susceptibility%20loci&journal=Mol%20Neurodegener&doi=10.1186%2Fs13024-018-0267-3&volume=13&publication_year=2018&author=Sanchez-Contreras%2CMY&author=Kouri%2CN&author=Cook%2CCN&author=Serie%2CDJ&author=Heckman%2CMG&author=Finch%2CNA&author=Caselli%2CRJ&author=Uitti%2CRJ&author=Wszolek%2CZK&author=Graff-Radford%2CN"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="105."><p class="c-article-references__text" id="ref-CR105">Scheper W, Hoozemans JJ (2015) The unfolded protein response in neurodegenerative diseases: a neuropathological perspective. Acta Neuropathol 130:315–331. <a href="https://doi.org/10.1007/s00401-015-1462-8" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1007/s00401-015-1462-8">https://doi.org/10.1007/s00401-015-1462-8</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1007/s00401-015-1462-8" data-track-item_id="10.1007/s00401-015-1462-8" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1007/s00401-015-1462-8" aria-label="Article reference 105" data-doi="10.1007/s00401-015-1462-8">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=26210990" aria-label="PubMed reference 105">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4541706" aria-label="PubMed Central reference 105">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC2MXht1amtb%2FJ" aria-label="CAS reference 105">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 105" href="http://scholar.google.com/scholar_lookup?&title=The%20unfolded%20protein%20response%20in%20neurodegenerative%20diseases%3A%20a%20neuropathological%20perspective&journal=Acta%20Neuropathol&doi=10.1007%2Fs00401-015-1462-8&volume=130&pages=315-331&publication_year=2015&author=Scheper%2CW&author=Hoozemans%2CJJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="106."><p class="c-article-references__text" id="ref-CR106">Schulkens IA, Castricum KC, Weijers EM, Koolwijk P, Griffioen AW, Thijssen VL (2014) Expression, regulation and function of human metallothioneins in endothelial cells. J Vasc Res 51:231–238. <a href="https://doi.org/10.1159/000365550" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1159/000365550">https://doi.org/10.1159/000365550</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1159/000365550" data-track-item_id="10.1159/000365550" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1159%2F000365550" aria-label="Article reference 106" data-doi="10.1159/000365550">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=25116857" aria-label="PubMed reference 106">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC2cXhsVyqtrnJ" aria-label="CAS reference 106">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 106" href="http://scholar.google.com/scholar_lookup?&title=Expression%2C%20regulation%20and%20function%20of%20human%20metallothioneins%20in%20endothelial%20cells&journal=J%20Vasc%20Res&doi=10.1159%2F000365550&volume=51&pages=231-238&publication_year=2014&author=Schulkens%2CIA&author=Castricum%2CKC&author=Weijers%2CEM&author=Koolwijk%2CP&author=Griffioen%2CAW&author=Thijssen%2CVL"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="107."><p class="c-article-references__text" id="ref-CR107">Seo JS, Lee S, Shin JY, Hwang YJ, Cho H, Yoo SK et al (2017) Transcriptome analyses of chronic traumatic encephalopathy show alterations in protein phosphatase expression associated with tauopathy. Exp Mol Med 49:e333. <a href="https://doi.org/10.1038/emm.2017.56" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1038/emm.2017.56">https://doi.org/10.1038/emm.2017.56</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/emm.2017.56" data-track-item_id="10.1038/emm.2017.56" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Femm.2017.56" aria-label="Article reference 107" data-doi="10.1038/emm.2017.56">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=28524178" aria-label="PubMed reference 107">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5454448" aria-label="PubMed Central reference 107">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC2sXlslegt70%3D" aria-label="CAS reference 107">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 107" href="http://scholar.google.com/scholar_lookup?&title=Transcriptome%20analyses%20of%20chronic%20traumatic%20encephalopathy%20show%20alterations%20in%20protein%20phosphatase%20expression%20associated%20with%20tauopathy&journal=Exp%20Mol%20Med&doi=10.1038%2Femm.2017.56&volume=49&publication_year=2017&author=Seo%2CJS&author=Lee%2CS&author=Shin%2CJY&author=Hwang%2CYJ&author=Cho%2CH&author=Yoo%2CSK&author=Kim%2CY&author=Lim%2CS&author=Kim%2CYK&author=Hwang%2CEM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="108."><p class="c-article-references__text" id="ref-CR108">Shah H, CW Y, Castellanos R, Pandya C, Giles Z (2015) RAPiD—an agile and dependable RNA-Seq framework. The 65th annual meeting of the American society of human genetics, City</p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="109."><p class="c-article-references__text" id="ref-CR109">Silva MC, Cheng C, Mair W, Almeida S, Fong H, Biswas MHU et al (2016) Human iPSC-derived neuronal model of Tau-A152T frontotemporal dementia reveals Tau-mediated mechanisms of neuronal vulnerability. Stem Cell Reports 7:325–340. <a href="https://doi.org/10.1016/j.stemcr.2016.08.001" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1016/j.stemcr.2016.08.001">https://doi.org/10.1016/j.stemcr.2016.08.001</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.stemcr.2016.08.001" data-track-item_id="10.1016/j.stemcr.2016.08.001" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.stemcr.2016.08.001" aria-label="Article reference 109" data-doi="10.1016/j.stemcr.2016.08.001">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=27594585" aria-label="PubMed reference 109">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5032560" aria-label="PubMed Central reference 109">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC28XhsVyqu7fL" aria-label="CAS reference 109">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 109" href="http://scholar.google.com/scholar_lookup?&title=Human%20iPSC-derived%20neuronal%20model%20of%20Tau-A152T%20frontotemporal%20dementia%20reveals%20Tau-mediated%20mechanisms%20of%20neuronal%20vulnerability&journal=Stem%20Cell%20Reports&doi=10.1016%2Fj.stemcr.2016.08.001&volume=7&pages=325-340&publication_year=2016&author=Silva%2CMC&author=Cheng%2CC&author=Mair%2CW&author=Almeida%2CS&author=Fong%2CH&author=Biswas%2CMHU&author=Zhang%2CZ&author=Huang%2CY&author=Temple%2CS&author=Coppola%2CG"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="110."><p class="c-article-references__text" id="ref-CR110">Smajic S, Prada-Medina CA, Landoulsi Z, Ghelfi J, Delcambre S, Dietrich C et al (2022) Single-cell sequencing of human midbrain reveals glial activation and a Parkinson-specific neuronal state. Brain 145:964–978. <a href="https://doi.org/10.1093/brain/awab446" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1093/brain/awab446">https://doi.org/10.1093/brain/awab446</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1093/brain/awab446" data-track-item_id="10.1093/brain/awab446" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1093%2Fbrain%2Fawab446" aria-label="Article reference 110" data-doi="10.1093/brain/awab446">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=34919646" aria-label="PubMed reference 110">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 110" href="http://scholar.google.com/scholar_lookup?&title=Single-cell%20sequencing%20of%20human%20midbrain%20reveals%20glial%20activation%20and%20a%20Parkinson-specific%20neuronal%20state&journal=Brain&doi=10.1093%2Fbrain%2Fawab446&volume=145&pages=964-978&publication_year=2022&author=Smajic%2CS&author=Prada-Medina%2CCA&author=Landoulsi%2CZ&author=Ghelfi%2CJ&author=Delcambre%2CS&author=Dietrich%2CC&author=Jarazo%2CJ&author=Henck%2CJ&author=Balachandran%2CS&author=Pachchek%2CS"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="111."><p class="c-article-references__text" id="ref-CR111">Smith HL, Freeman OJ, Butcher AJ, Holmqvist S, Humoud I, Schatzl T et al (2020) Astrocyte unfolded protein response induces a specific reactivity state that causes non-cell-autonomous neuronal degeneration. Neuron 105(855–866):e855. <a href="https://doi.org/10.1016/j.neuron.2019.12.014" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1016/j.neuron.2019.12.014">https://doi.org/10.1016/j.neuron.2019.12.014</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.neuron.2019.12.014" data-track-item_id="10.1016/j.neuron.2019.12.014" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.neuron.2019.12.014" aria-label="Article reference 111" data-doi="10.1016/j.neuron.2019.12.014">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXmt1ehtw%3D%3D" aria-label="CAS reference 111">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 111" href="http://scholar.google.com/scholar_lookup?&title=Astrocyte%20unfolded%20protein%20response%20induces%20a%20specific%20reactivity%20state%20that%20causes%20non-cell-autonomous%20neuronal%20degeneration&journal=Neuron&doi=10.1016%2Fj.neuron.2019.12.014&volume=105&issue=855%E2%80%93866&publication_year=2020&author=Smith%2CHL&author=Freeman%2COJ&author=Butcher%2CAJ&author=Holmqvist%2CS&author=Humoud%2CI&author=Schatzl%2CT&author=Hughes%2CDT&author=Verity%2CNC&author=Swinden%2CDP&author=Hayes%2CJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="112."><p class="c-article-references__text" id="ref-CR112">Srivastava SP, Kumar KU, Kaufman RJ (1998) Phosphorylation of eukaryotic translation initiation factor 2 mediates apoptosis in response to activation of the double-stranded RNA-dependent protein kinase. J Biol Chem 273:2416–2423. <a href="https://doi.org/10.1074/jbc.273.4.2416" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1074/jbc.273.4.2416">https://doi.org/10.1074/jbc.273.4.2416</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1074/jbc.273.4.2416" data-track-item_id="10.1074/jbc.273.4.2416" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1074%2Fjbc.273.4.2416" aria-label="Article reference 112" data-doi="10.1074/jbc.273.4.2416">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=9442091" aria-label="PubMed reference 112">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DyaK1cXnsVyhsA%3D%3D" aria-label="CAS reference 112">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 112" href="http://scholar.google.com/scholar_lookup?&title=Phosphorylation%20of%20eukaryotic%20translation%20initiation%20factor%202%20mediates%20apoptosis%20in%20response%20to%20activation%20of%20the%20double-stranded%20RNA-dependent%20protein%20kinase&journal=J%20Biol%20Chem&doi=10.1074%2Fjbc.273.4.2416&volume=273&pages=2416-2423&publication_year=1998&author=Srivastava%2CSP&author=Kumar%2CKU&author=Kaufman%2CRJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="113."><p class="c-article-references__text" id="ref-CR113">Steiner B, Mandelkow EM, Biernat J, Gustke N, Meyer HE, Schmidt B et al (1990) Phosphorylation of microtubule-associated protein tau: identification of the site for Ca2(+)-calmodulin dependent kinase and relationship with tau phosphorylation in Alzheimer tangles. EMBO J 9:3539–3544. <a href="https://doi.org/10.1002/j.1460-2075.1990.tb07563.x" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1002/j.1460-2075.1990.tb07563.x">https://doi.org/10.1002/j.1460-2075.1990.tb07563.x</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1002/j.1460-2075.1990.tb07563.x" data-track-item_id="10.1002/j.1460-2075.1990.tb07563.x" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2Fj.1460-2075.1990.tb07563.x" aria-label="Article reference 113" data-doi="10.1002/j.1460-2075.1990.tb07563.x">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=2120043" aria-label="PubMed reference 113">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC552103" aria-label="PubMed Central reference 113">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DyaK3cXmt1yrt7g%3D" aria-label="CAS reference 113">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 113" href="http://scholar.google.com/scholar_lookup?&title=Phosphorylation%20of%20microtubule-associated%20protein%20tau%3A%20identification%20of%20the%20site%20for%20Ca2%28%2B%29-calmodulin%20dependent%20kinase%20and%20relationship%20with%20tau%20phosphorylation%20in%20Alzheimer%20tangles&journal=EMBO%20J&doi=10.1002%2Fj.1460-2075.1990.tb07563.x&volume=9&pages=3539-3544&publication_year=1990&author=Steiner%2CB&author=Mandelkow%2CEM&author=Biernat%2CJ&author=Gustke%2CN&author=Meyer%2CHE&author=Schmidt%2CB&author=Mieskes%2CG&author=Soling%2CHD&author=Drechsel%2CD&author=Kirschner%2CMW"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="114."><p class="c-article-references__text" id="ref-CR114">Stuart T, Butler A, Hoffman P, Hafemeister C, Papalexi E, Mauck WM 3rd et al (2019) Comprehensive integration of single-cell data. Cell 177(1888–1902):e1821. <a href="https://doi.org/10.1016/j.cell.2019.05.031" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1016/j.cell.2019.05.031">https://doi.org/10.1016/j.cell.2019.05.031</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.cell.2019.05.031" data-track-item_id="10.1016/j.cell.2019.05.031" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.cell.2019.05.031" aria-label="Article reference 114" data-doi="10.1016/j.cell.2019.05.031">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC1MXhtFens77L" aria-label="CAS reference 114">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 114" href="http://scholar.google.com/scholar_lookup?&title=Comprehensive%20integration%20of%20single-cell%20data&journal=Cell&doi=10.1016%2Fj.cell.2019.05.031&volume=177&issue=1888%E2%80%931902&publication_year=2019&author=Stuart%2CT&author=Butler%2CA&author=Hoffman%2CP&author=Hafemeister%2CC&author=Papalexi%2CE&author=Mauck%2CWM&author=Hao%2CY&author=Stoeckius%2CM&author=Smibert%2CP&author=Satija%2CR"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="115."><p class="c-article-references__text" id="ref-CR115">Stutzbach LD, Xie SX, Naj AC, Albin R, Gilman S, Group PSPGS et al (2013) The unfolded protein response is activated in disease-affected brain regions in progressive supranuclear palsy and Alzheimer’s disease. Acta Neuropathol Commun 1:31. <a href="https://doi.org/10.1186/2051-5960-1-31" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1186/2051-5960-1-31">https://doi.org/10.1186/2051-5960-1-31</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/2051-5960-1-31" data-track-item_id="10.1186/2051-5960-1-31" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/2051-5960-1-31" aria-label="Article reference 115" data-doi="10.1186/2051-5960-1-31">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=24252572" aria-label="PubMed reference 115">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3893579" aria-label="PubMed Central reference 115">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 115" href="http://scholar.google.com/scholar_lookup?&title=The%20unfolded%20protein%20response%20is%20activated%20in%20disease-affected%20brain%20regions%20in%20progressive%20supranuclear%20palsy%20and%20Alzheimer%27s%20disease&journal=Acta%20Neuropathol%20Commun&doi=10.1186%2F2051-5960-1-31&volume=1&publication_year=2013&author=Stutzbach%2CLD&author=Xie%2CSX&author=Naj%2CAC&author=Albin%2CR&author=Gilman%2CS&author=Lee%2CVM&author=Trojanowski%2CJQ&author=Devlin%2CB&author=Schellenberg%2CGD"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="116."><p class="c-article-references__text" id="ref-CR116">Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA et al (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 102:15545–15550. <a href="https://doi.org/10.1073/pnas.0506580102" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1073/pnas.0506580102">https://doi.org/10.1073/pnas.0506580102</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1073/pnas.0506580102" data-track-item_id="10.1073/pnas.0506580102" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1073%2Fpnas.0506580102" aria-label="Article reference 116" data-doi="10.1073/pnas.0506580102">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=16199517" aria-label="PubMed reference 116">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1239896" aria-label="PubMed Central reference 116">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD2MXht1ShtrnO" aria-label="CAS reference 116">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 116" href="http://scholar.google.com/scholar_lookup?&title=Gene%20set%20enrichment%20analysis%3A%20a%20knowledge-based%20approach%20for%20interpreting%20genome-wide%20expression%20profiles&journal=Proc%20Natl%20Acad%20Sci%20U%20S%20A&doi=10.1073%2Fpnas.0506580102&volume=102&pages=15545-15550&publication_year=2005&author=Subramanian%2CA&author=Tamayo%2CP&author=Mootha%2CVK&author=Mukherjee%2CS&author=Ebert%2CBL&author=Gillette%2CMA&author=Paulovich%2CA&author=Pomeroy%2CSL&author=Golub%2CTR&author=Lander%2CES"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="117."><p class="c-article-references__text" id="ref-CR117">Sweeney MD, Sagare AP, Zlokovic BV (2018) Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol 14:133–150. <a href="https://doi.org/10.1038/nrneurol.2017.188" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1038/nrneurol.2017.188">https://doi.org/10.1038/nrneurol.2017.188</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/nrneurol.2017.188" data-track-item_id="10.1038/nrneurol.2017.188" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fnrneurol.2017.188" aria-label="Article reference 117" data-doi="10.1038/nrneurol.2017.188">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=29377008" aria-label="PubMed reference 117">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5829048" aria-label="PubMed Central reference 117">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC1cXhvVeqtbk%3D" aria-label="CAS reference 117">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 117" href="http://scholar.google.com/scholar_lookup?&title=Blood-brain%20barrier%20breakdown%20in%20Alzheimer%20disease%20and%20other%20neurodegenerative%20disorders&journal=Nat%20Rev%20Neurol&doi=10.1038%2Fnrneurol.2017.188&volume=14&pages=133-150&publication_year=2018&author=Sweeney%2CMD&author=Sagare%2CAP&author=Zlokovic%2CBV"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="118."><p class="c-article-references__text" id="ref-CR118">Szumilas M (2010) Explaining odds ratios. J Can Acad Child Adolesc Psychiatry 19:227–229</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=20842279" aria-label="PubMed reference 118">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2938757" aria-label="PubMed Central reference 118">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 118" href="http://scholar.google.com/scholar_lookup?&title=Explaining%20odds%20ratios&journal=J%20Can%20Acad%20Child%20Adolesc%20Psychiatry&volume=19&pages=227-229&publication_year=2010&author=Szumilas%2CM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="119."><p class="c-article-references__text" id="ref-CR119">Taniuchi S, Miyake M, Tsugawa K, Oyadomari M, Oyadomari S (2016) Integrated stress response of vertebrates is regulated by four eIF2alpha kinases. Sci Rep 6:32886. <a href="https://doi.org/10.1038/srep32886" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1038/srep32886">https://doi.org/10.1038/srep32886</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/srep32886" data-track-item_id="10.1038/srep32886" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fsrep32886" aria-label="Article reference 119" data-doi="10.1038/srep32886">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=27633668" aria-label="PubMed reference 119">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5025754" aria-label="PubMed Central reference 119">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC28XhsFentLrP" aria-label="CAS reference 119">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 119" href="http://scholar.google.com/scholar_lookup?&title=Integrated%20stress%20response%20of%20vertebrates%20is%20regulated%20by%20four%20eIF2alpha%20kinases&journal=Sci%20Rep&doi=10.1038%2Fsrep32886&volume=6&publication_year=2016&author=Taniuchi%2CS&author=Miyake%2CM&author=Tsugawa%2CK&author=Oyadomari%2CM&author=Oyadomari%2CS"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="120."><p class="c-article-references__text" id="ref-CR120">Trabzuni D, Wray S, Vandrovcova J, Ramasamy A, Walker R, Smith C et al (2012) MAPT expression and splicing is differentially regulated by brain region: relation to genotype and implication for tauopathies. Hum Mol Genet 21:4094–4103. <a href="https://doi.org/10.1093/hmg/dds238" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1093/hmg/dds238">https://doi.org/10.1093/hmg/dds238</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1093/hmg/dds238" data-track-item_id="10.1093/hmg/dds238" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1093%2Fhmg%2Fdds238" aria-label="Article reference 120" data-doi="10.1093/hmg/dds238">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=22723018" aria-label="PubMed reference 120">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3428157" aria-label="PubMed Central reference 120">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BC38Xht1yntrzF" aria-label="CAS reference 120">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 120" href="http://scholar.google.com/scholar_lookup?&title=MAPT%20expression%20and%20splicing%20is%20differentially%20regulated%20by%20brain%20region%3A%20relation%20to%20genotype%20and%20implication%20for%20tauopathies&journal=Hum%20Mol%20Genet&doi=10.1093%2Fhmg%2Fdds238&volume=21&pages=4094-4103&publication_year=2012&author=Trabzuni%2CD&author=Wray%2CS&author=Vandrovcova%2CJ&author=Ramasamy%2CA&author=Walker%2CR&author=Smith%2CC&author=Luk%2CC&author=Gibbs%2CJR&author=Dillman%2CA&author=Hernandez%2CDG"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="121."><p class="c-article-references__text" id="ref-CR121">Unterberger U, Hoftberger R, Gelpi E, Flicker H, Budka H, Voigtlander T (2006) Endoplasmic reticulum stress features are prominent in Alzheimer disease but not in prion diseases in vivo. J Neuropathol Exp Neurol 65:348–357. <a href="https://doi.org/10.1097/01.jnen.0000218445.30535.6f" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1097/01.jnen.0000218445.30535.6f">https://doi.org/10.1097/01.jnen.0000218445.30535.6f</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1097/01.jnen.0000218445.30535.6f" data-track-item_id="10.1097/01.jnen.0000218445.30535.6f" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1097%2F01.jnen.0000218445.30535.6f" aria-label="Article reference 121" data-doi="10.1097/01.jnen.0000218445.30535.6f">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=16691116" aria-label="PubMed reference 121">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD28XltFequ7w%3D" aria-label="CAS reference 121">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 121" href="http://scholar.google.com/scholar_lookup?&title=Endoplasmic%20reticulum%20stress%20features%20are%20prominent%20in%20Alzheimer%20disease%20but%20not%20in%20prion%20diseases%20in%20vivo&journal=J%20Neuropathol%20Exp%20Neurol&doi=10.1097%2F01.jnen.0000218445.30535.6f&volume=65&pages=348-357&publication_year=2006&author=Unterberger%2CU&author=Hoftberger%2CR&author=Gelpi%2CE&author=Flicker%2CH&author=Budka%2CH&author=Voigtlander%2CT"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="122."><p class="c-article-references__text" id="ref-CR122">Utal AK, Stopka AL, Roy M, Coleman PD (1998) PEP-19 immunohistochemistry defines the basal ganglia and associated structures in the adult human brain, and is dramatically reduced in Huntington’s disease. Neuroscience 86:1055–1063. <a href="https://doi.org/10.1016/s0306-4522(98)00130-4" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1016/s0306-4522(98)00130-4">https://doi.org/10.1016/s0306-4522(98)00130-4</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/s0306-4522(98)00130-4" data-track-item_id="10.1016/s0306-4522(98)00130-4" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fs0306-4522%2898%2900130-4" aria-label="Article reference 122" data-doi="10.1016/s0306-4522(98)00130-4">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=9697113" aria-label="PubMed reference 122">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DyaK1cXkslWgu7o%3D" aria-label="CAS reference 122">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 122" href="http://scholar.google.com/scholar_lookup?&title=PEP-19%20immunohistochemistry%20defines%20the%20basal%20ganglia%20and%20associated%20structures%20in%20the%20adult%20human%20brain%2C%20and%20is%20dramatically%20reduced%20in%20Huntington%27s%20disease&journal=Neuroscience&doi=10.1016%2Fs0306-4522%2898%2900130-4&volume=86&pages=1055-1063&publication_year=1998&author=Utal%2CAK&author=Stopka%2CAL&author=Roy%2CM&author=Coleman%2CPD"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="123."><p class="c-article-references__text" id="ref-CR123">Vallejo J, Saigusa R, Gulati R, Armstrong Suthahar SS, Suryawanshi V, Alimadadi A et al (2022) Combined protein and transcript single-cell RNA sequencing in human peripheral blood mononuclear cells. BMC Biol 20:193. <a href="https://doi.org/10.1186/s12915-022-01382-4" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1186/s12915-022-01382-4">https://doi.org/10.1186/s12915-022-01382-4</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/s12915-022-01382-4" data-track-item_id="10.1186/s12915-022-01382-4" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/s12915-022-01382-4" aria-label="Article reference 123" data-doi="10.1186/s12915-022-01382-4">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=36045343" aria-label="PubMed reference 123">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9434837" aria-label="PubMed Central reference 123">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB38Xitlaht7zN" aria-label="CAS reference 123">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 123" href="http://scholar.google.com/scholar_lookup?&title=Combined%20protein%20and%20transcript%20single-cell%20RNA%20sequencing%20in%20human%20peripheral%20blood%20mononuclear%20cells&journal=BMC%20Biol&doi=10.1186%2Fs12915-022-01382-4&volume=20&publication_year=2022&author=Vallejo%2CJ&author=Saigusa%2CR&author=Gulati%2CR&author=Armstrong%20Suthahar%2CSS&author=Suryawanshi%2CV&author=Alimadadi%2CA&author=Durant%2CCP&author=Ghosheh%2CY&author=Roy%2CP&author=Ehinger%2CE"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="124."><p class="c-article-references__text" id="ref-CR124">Weitzman JB, Fiette L, Matsuo K, Yaniv M (2000) JunD protects cells from p53-dependent senescence and apoptosis. Mol Cell 6:1109–1119. <a href="https://doi.org/10.1016/s1097-2765(00)00109-x" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1016/s1097-2765(00)00109-x">https://doi.org/10.1016/s1097-2765(00)00109-x</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/s1097-2765(00)00109-x" data-track-item_id="10.1016/s1097-2765(00)00109-x" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fs1097-2765%2800%2900109-x" aria-label="Article reference 124" data-doi="10.1016/s1097-2765(00)00109-x">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=11106750" aria-label="PubMed reference 124">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD3cXosV2mtrg%3D" aria-label="CAS reference 124">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 124" href="http://scholar.google.com/scholar_lookup?&title=JunD%20protects%20cells%20from%20p53-dependent%20senescence%20and%20apoptosis&journal=Mol%20Cell&doi=10.1016%2Fs1097-2765%2800%2900109-x&volume=6&pages=1109-1119&publication_year=2000&author=Weitzman%2CJB&author=Fiette%2CL&author=Matsuo%2CK&author=Yaniv%2CM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="125."><p class="c-article-references__text" id="ref-CR125">Williams DR, Holton JL, Strand C, Pittman A, de Silva R, Lees AJ et al (2007) Pathological tau burden and distribution distinguishes progressive supranuclear palsy-parkinsonism from Richardson’s syndrome. Brain 130:1566–1576. <a href="https://doi.org/10.1093/brain/awm104" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1093/brain/awm104">https://doi.org/10.1093/brain/awm104</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1093/brain/awm104" data-track-item_id="10.1093/brain/awm104" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1093%2Fbrain%2Fawm104" aria-label="Article reference 125" data-doi="10.1093/brain/awm104">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=17525140" aria-label="PubMed reference 125">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 125" href="http://scholar.google.com/scholar_lookup?&title=Pathological%20tau%20burden%20and%20distribution%20distinguishes%20progressive%20supranuclear%20palsy-parkinsonism%20from%20Richardson%E2%80%99s%20syndrome&journal=Brain&doi=10.1093%2Fbrain%2Fawm104&volume=130&pages=1566-1576&publication_year=2007&author=Williams%2CDR&author=Holton%2CJL&author=Strand%2CC&author=Pittman%2CA&author=Silva%2CR&author=Lees%2CAJ&author=Revesz%2CT"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="126."><p class="c-article-references__text" id="ref-CR126">Wilson DM 3rd, Cookson MR, Van Den Bosch L, Zetterberg H, Holtzman DM, Dewachter I (2023) Hallmarks of neurodegenerative diseases. Cell 186:693–714. <a href="https://doi.org/10.1016/j.cell.2022.12.032" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1016/j.cell.2022.12.032">https://doi.org/10.1016/j.cell.2022.12.032</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.cell.2022.12.032" data-track-item_id="10.1016/j.cell.2022.12.032" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.cell.2022.12.032" aria-label="Article reference 126" data-doi="10.1016/j.cell.2022.12.032">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=36803602" aria-label="PubMed reference 126">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3sXjtl2lt7Y%3D" aria-label="CAS reference 126">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 126" href="http://scholar.google.com/scholar_lookup?&title=Hallmarks%20of%20neurodegenerative%20diseases&journal=Cell&doi=10.1016%2Fj.cell.2022.12.032&volume=186&pages=693-714&publication_year=2023&author=Wilson%2CDM&author=Cookson%2CMR&author=Bosch%2CL&author=Zetterberg%2CH&author=Holtzman%2CDM&author=Dewachter%2CI"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="127."><p class="c-article-references__text" id="ref-CR127">Wojtas AM, Carlomagno Y, Sens JP, Kang SS, Jensen TD, Kurti A et al (2020) Clusterin ameliorates tau pathology in vivo by inhibiting fibril formation. Acta Neuropathol Commun 8:210. <a href="https://doi.org/10.1186/s40478-020-01079-1" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1186/s40478-020-01079-1">https://doi.org/10.1186/s40478-020-01079-1</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/s40478-020-01079-1" data-track-item_id="10.1186/s40478-020-01079-1" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/s40478-020-01079-1" aria-label="Article reference 127" data-doi="10.1186/s40478-020-01079-1">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33261653" aria-label="PubMed reference 127">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708249" aria-label="PubMed Central reference 127">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXis12lt7jO" aria-label="CAS reference 127">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 127" href="http://scholar.google.com/scholar_lookup?&title=Clusterin%20ameliorates%20tau%20pathology%20in%20vivo%20by%20inhibiting%20fibril%20formation&journal=Acta%20Neuropathol%20Commun&doi=10.1186%2Fs40478-020-01079-1&volume=8&publication_year=2020&author=Wojtas%2CAM&author=Carlomagno%2CY&author=Sens%2CJP&author=Kang%2CSS&author=Jensen%2CTD&author=Kurti%2CA&author=Baker%2CKE&author=Berry%2CTJ&author=Phillips%2CVR&author=Castanedes%2CMC"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="128."><p class="c-article-references__text" id="ref-CR128">Xiao J, Perry G, Troncoso J, Monteiro MJ (1996) alpha-calcium-calmodulin-dependent kinase II is associated with paired helical filaments of Alzheimer’s disease. J Neuropathol Exp Neurol 55:954–963. <a href="https://doi.org/10.1097/00005072-199609000-00002" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1097/00005072-199609000-00002">https://doi.org/10.1097/00005072-199609000-00002</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1097/00005072-199609000-00002" data-track-item_id="10.1097/00005072-199609000-00002" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1097%2F00005072-199609000-00002" aria-label="Article reference 128" data-doi="10.1097/00005072-199609000-00002">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=8800091" aria-label="PubMed reference 128">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DyaK2sXpt1WhsA%3D%3D" aria-label="CAS reference 128">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 128" href="http://scholar.google.com/scholar_lookup?&title=alpha-calcium-calmodulin-dependent%20kinase%20II%20is%20associated%20with%20paired%20helical%20filaments%20of%20Alzheimer%E2%80%99s%20disease&journal=J%20Neuropathol%20Exp%20Neurol&doi=10.1097%2F00005072-199609000-00002&volume=55&pages=954-963&publication_year=1996&author=Xiao%2CJ&author=Perry%2CG&author=Troncoso%2CJ&author=Monteiro%2CMJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="129."><p class="c-article-references__text" id="ref-CR129">Yan C, Jiang J, Yang Y, Geng X, Dong W (2022) The function of VAMP2 in mediating membrane fusion: an overview. Front Mol Neurosci 15:948160. <a href="https://doi.org/10.3389/fnmol.2022.948160" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.3389/fnmol.2022.948160">https://doi.org/10.3389/fnmol.2022.948160</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.3389/fnmol.2022.948160" data-track-item_id="10.3389/fnmol.2022.948160" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.3389%2Ffnmol.2022.948160" aria-label="Article reference 129" data-doi="10.3389/fnmol.2022.948160">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=36618823" aria-label="PubMed reference 129">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9816800" aria-label="PubMed Central reference 129">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3sXhtVOqt77N" aria-label="CAS reference 129">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 129" href="http://scholar.google.com/scholar_lookup?&title=The%20function%20of%20VAMP2%20in%20mediating%20membrane%20fusion%3A%20an%20overview&journal=Front%20Mol%20Neurosci&doi=10.3389%2Ffnmol.2022.948160&volume=15&publication_year=2022&author=Yan%2CC&author=Jiang%2CJ&author=Yang%2CY&author=Geng%2CX&author=Dong%2CW"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="130."><p class="c-article-references__text" id="ref-CR130">Yanaizu M, Washizu C, Nukina N, Satoh JI, Kino Y (2020) CELF2 regulates the species-specific alternative splicing of TREM2. Sci Rep 10:17995. <a href="https://doi.org/10.1038/s41598-020-75057-x" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1038/s41598-020-75057-x">https://doi.org/10.1038/s41598-020-75057-x</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/s41598-020-75057-x" data-track-item_id="10.1038/s41598-020-75057-x" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fs41598-020-75057-x" aria-label="Article reference 130" data-doi="10.1038/s41598-020-75057-x">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=33093587" aria-label="PubMed reference 130">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582162" aria-label="PubMed Central reference 130">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXitF2jsbjL" aria-label="CAS reference 130">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 130" href="http://scholar.google.com/scholar_lookup?&title=CELF2%20regulates%20the%20species-specific%20alternative%20splicing%20of%20TREM2&journal=Sci%20Rep&doi=10.1038%2Fs41598-020-75057-x&volume=10&publication_year=2020&author=Yanaizu%2CM&author=Washizu%2CC&author=Nukina%2CN&author=Satoh%2CJI&author=Kino%2CY"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="131."><p class="c-article-references__text" id="ref-CR131">Yoshimura Y, Ichinose T, Yamauchi T (2003) Phosphorylation of tau protein to sites found in Alzheimer’s disease brain is catalyzed by Ca2+/calmodulin-dependent protein kinase II as demonstrated tandem mass spectrometry. Neurosci Lett 353:185–188. <a href="https://doi.org/10.1016/j.neulet.2003.09.037" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.1016/j.neulet.2003.09.037">https://doi.org/10.1016/j.neulet.2003.09.037</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.neulet.2003.09.037" data-track-item_id="10.1016/j.neulet.2003.09.037" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.neulet.2003.09.037" aria-label="Article reference 131" data-doi="10.1016/j.neulet.2003.09.037">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=14665412" aria-label="PubMed reference 131">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD3sXps1Grtrw%3D" aria-label="CAS reference 131">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 131" href="http://scholar.google.com/scholar_lookup?&title=Phosphorylation%20of%20tau%20protein%20to%20sites%20found%20in%20Alzheimer%E2%80%99s%20disease%20brain%20is%20catalyzed%20by%20Ca2%2B%2Fcalmodulin-dependent%20protein%20kinase%20II%20as%20demonstrated%20tandem%20mass%20spectrometry&journal=Neurosci%20Lett&doi=10.1016%2Fj.neulet.2003.09.037&volume=353&pages=185-188&publication_year=2003&author=Yoshimura%2CY&author=Ichinose%2CT&author=Yamauchi%2CT"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="132."><p class="c-article-references__text" id="ref-CR132">Yuan A, Nixon RA (2021) Neurofilament proteins as biomarkers to monitor neurological diseases and the efficacy of therapies. Front Neurosci 15:689938. <a href="https://doi.org/10.3389/fnins.2021.689938" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.3389/fnins.2021.689938">https://doi.org/10.3389/fnins.2021.689938</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.3389/fnins.2021.689938" data-track-item_id="10.3389/fnins.2021.689938" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.3389%2Ffnins.2021.689938" aria-label="Article reference 132" data-doi="10.3389/fnins.2021.689938">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=34646114" aria-label="PubMed reference 132">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8503617" aria-label="PubMed Central reference 132">PubMed Central</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 132" href="http://scholar.google.com/scholar_lookup?&title=Neurofilament%20proteins%20as%20biomarkers%20to%20monitor%20neurological%20diseases%20and%20the%20efficacy%20of%20therapies&journal=Front%20Neurosci&doi=10.3389%2Ffnins.2021.689938&volume=15&publication_year=2021&author=Yuan%2CA&author=Nixon%2CRA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="133."><p class="c-article-references__text" id="ref-CR133">Zarate SC, Traetta ME, Codagnone MG, Seilicovich A, Reines AG (2019) Humanin, a mitochondrial-derived peptide released by astrocytes, prevents synapse loss in hippocampal neurons. Front Aging Neurosci 11:123. <a href="https://doi.org/10.3389/fnagi.2019.00123" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="10.3389/fnagi.2019.00123">https://doi.org/10.3389/fnagi.2019.00123</a></p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.3389/fnagi.2019.00123" data-track-item_id="10.3389/fnagi.2019.00123" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.3389%2Ffnagi.2019.00123" aria-label="Article reference 133" data-doi="10.3389/fnagi.2019.00123">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=31214013" aria-label="PubMed reference 133">PubMed</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555273" aria-label="PubMed Central reference 133">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BB3cXjs1yjs74%3D" aria-label="CAS reference 133">CAS</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 133" href="http://scholar.google.com/scholar_lookup?&title=Humanin%2C%20a%20mitochondrial-derived%20peptide%20released%20by%20astrocytes%2C%20prevents%20synapse%20loss%20in%20hippocampal%20neurons&journal=Front%20Aging%20Neurosci&doi=10.3389%2Ffnagi.2019.00123&volume=11&publication_year=2019&author=Zarate%2CSC&author=Traetta%2CME&author=Codagnone%2CMG&author=Seilicovich%2CA&author=Reines%2CAG"> Google Scholar</a> </p></li></ol><p class="c-article-references__download u-hide-print"><a data-track="click" data-track-action="download citation references" data-track-label="link" rel="nofollow" href="https://citation-needed.springer.com/v2/references/10.1007/s00401-024-02823-w?format=refman&flavour=references">Download references<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-download-medium"></use></svg></a></p></div></div></div></section></div><section data-title="Acknowledgements"><div class="c-article-section" id="Ack1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Ack1">Acknowledgements</h2><div class="c-article-section__content" id="Ack1-content"><p>This work was supported by the Karen Strauss Cook Research Scholar Award to A.C.P and J.F.C, the National Institutes of Health (R01AG063819 and R01AG064020 to A.C.P, R01AG054008 and R01NS095252 to J.F.C, F32AG072837 to K.W. and NIA career development award P30AG066514), the Alzheimer’s Association (AARG22-973911 to A.C.P and AARF-22-974094 to K.W.), the Carolyn and Eugene Mercy Research Gift to A.C.P., the Alzheimer’s New Jersey to A.C.P, the Robert J. and Claire Pasarow Foundation to A.C.P., the Alexander Saint-Amand Scholar Award to J.F.C, the Department of Veterans Affairs (CX002342) to R.H.W. and N.J.M., and the Tau Consortium/Rainwater Foundation to J.F.C.</p></div></div></section><section data-title="Funding"><div class="c-article-section" id="Fun-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Fun">Funding</h2><div class="c-article-section__content" id="Fun-content"><p>This work was supported by the Karen Strauss Cook Research Scholar Award, National Institute of Neurological Disorders and Stroke, R01NS095252, John F. Crary, National Institute on Aging, R01AG063819, Ana C. Pereira, R01AG064020, Ana C. Pereira, R01AG054008, John F. Crary, F32AG072837, Kristen Whitney, P30AG066514, Alzheimer’s Association, AARG22-973911, Ana C. Pereira, AARF-22-974094, Kristen Whitney, Carolyn and Eugene Mercy Research Gift, Alzheimer’s New Jersey, Robert J. and Claire Pasarow Foundation, Tau Consortium, U.S. Department of Veterans Affairs, CX002342, Ruth H. Walker and Melissa J. Nirenberg.</p></div></div></section><section aria-labelledby="author-information" data-title="Author information"><div class="c-article-section" id="author-information-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="author-information">Author information</h2><div class="c-article-section__content" id="author-information-content"><h3 class="c-article__sub-heading" id="affiliations">Authors and Affiliations</h3><ol class="c-article-author-affiliation__list"><li id="Aff1"><p class="c-article-author-affiliation__address">Department of Pathology, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA</p><p class="c-article-author-affiliation__authors-list">Kristen Whitney, Diana K. Dangoor, Kurt Farrell, Margaret M. Krassner, Hadley W. Ressler, Thomas D. Christie, Shrishtee Kandoi & John F. Crary</p></li><li id="Aff2"><p class="c-article-author-affiliation__address">Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA</p><p class="c-article-author-affiliation__authors-list">Kristen Whitney, Abhijeet Sharma, Diana K. Dangoor, Kurt Farrell, Margaret M. Krassner, Hadley W. Ressler, Thomas D. Christie, Shrishtee Kandoi, Ana C. Pereira & John F. Crary</p></li><li id="Aff3"><p class="c-article-author-affiliation__address">Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA</p><p class="c-article-author-affiliation__authors-list">Kristen Whitney, Abhijeet Sharma, Diana K. Dangoor, Kurt Farrell, Margaret M. Krassner, Hadley W. Ressler, Thomas D. Christie, Shrishtee Kandoi, Ana C. Pereira & John F. Crary</p></li><li id="Aff4"><p class="c-article-author-affiliation__address">Neuropathology Brain Bank & Research Core, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA</p><p class="c-article-author-affiliation__authors-list">Kristen Whitney, Diana K. Dangoor, Kurt Farrell, Margaret M. Krassner, Hadley W. Ressler, Thomas D. Christie, Shrishtee Kandoi & John F. Crary</p></li><li id="Aff5"><p class="c-article-author-affiliation__address">Department of Artificial Intelligence & Human Health, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA</p><p class="c-article-author-affiliation__authors-list">Kristen Whitney, Diana K. Dangoor, Kurt Farrell, Margaret M. Krassner, Hadley W. Ressler, Thomas D. Christie, Shrishtee Kandoi & John F. Crary</p></li><li id="Aff6"><p class="c-article-author-affiliation__address">Mount Sinai Center for Transformative Disease Modeling, Department of Genetics and Genomic Sciences, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA</p><p class="c-article-author-affiliation__authors-list">Won-Min Song & Bin Zhang</p></li><li id="Aff7"><p class="c-article-author-affiliation__address">Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA</p><p class="c-article-author-affiliation__authors-list">Won-Min Song & Bin Zhang</p></li><li id="Aff8"><p class="c-article-author-affiliation__address">Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA</p><p class="c-article-author-affiliation__authors-list">Won-Min Song & Bin Zhang</p></li><li id="Aff9"><p class="c-article-author-affiliation__address">Department of Neurology, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue, New York, NY, 10029, USA</p><p class="c-article-author-affiliation__authors-list">Abhijeet Sharma, Ruth H. Walker, Melissa J. Nirenberg & Ana C. Pereira</p></li><li id="Aff10"><p class="c-article-author-affiliation__address">Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA</p><p class="c-article-author-affiliation__authors-list">Bin Zhang</p></li><li id="Aff11"><p class="c-article-author-affiliation__address">The Marlene and Paolo Fresco Institute for Parkinson’s and Movement Disorders, Department of Neurology, NYU Langone Health, New York, NY, USA</p><p class="c-article-author-affiliation__authors-list">Steven J. Frucht & Giulietta M. Riboldi</p></li><li id="Aff12"><p class="c-article-author-affiliation__address">Department of Neurology, James J. Peters Veterans Affairs Medical Center, Bronx, NY, 10468, USA</p><p class="c-article-author-affiliation__authors-list">Ruth H. Walker, Melissa J. Nirenberg & John F. Crary</p></li></ol><div class="u-js-hide u-hide-print" data-test="author-info"><span class="c-article__sub-heading">Authors</span><ol class="c-article-authors-search u-list-reset"><li id="auth-Kristen-Whitney-Aff1-Aff2-Aff3-Aff4-Aff5"><span class="c-article-authors-search__title u-h3 js-search-name">Kristen Whitney</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?dc.creator=Kristen%20Whitney" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Kristen%20Whitney" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="http://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22Kristen%20Whitney%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li><li id="auth-Won_Min-Song-Aff6-Aff7-Aff8"><span class="c-article-authors-search__title u-h3 js-search-name">Won-Min Song</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?dc.creator=Won-Min%20Song" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Won-Min%20Song" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="http://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22Won-Min%20Song%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li><li id="auth-Abhijeet-Sharma-Aff2-Aff3-Aff9"><span class="c-article-authors-search__title u-h3 js-search-name">Abhijeet Sharma</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?dc.creator=Abhijeet%20Sharma" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Abhijeet%20Sharma" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="http://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22Abhijeet%20Sharma%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li><li id="auth-Diana_K_-Dangoor-Aff1-Aff2-Aff3-Aff4-Aff5"><span class="c-article-authors-search__title u-h3 js-search-name">Diana K. 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Crary</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?dc.creator=John%20F.%20Crary" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=John%20F.%20Crary" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="http://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22John%20F.%20Crary%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li></ol></div><h3 class="c-article__sub-heading" id="contributions">Contributions</h3><p>A.S, A.C.P, K.W., and J.F.C conceptualized and designed the experiments. A.S generated the snRNA-seq data with support from K.F. W.S, A.S, K.W., M.M.K, S.K. and H.W. analyzed snRNA-seq data and visualized results. K.W, K.F, D.K.D., M.M.K., and T.C. generated neuropathological data and performed immunohistochemical analysis. B.Z provided data analysis tools. All authors read and approved the final version of the manuscript.</p><h3 class="c-article__sub-heading" id="corresponding-author">Corresponding authors</h3><p id="corresponding-author-list">Correspondence to <a id="corresp-c1" href="mailto:won-min.song@mssm.edu">Won-Min Song</a>, <a id="corresp-c2" href="mailto:ana.pereira@mssm.edu">Ana C. Pereira</a> or <a id="corresp-c3" href="mailto:john.crary@mountsinai.org">John F. 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id="citeas">Cite this article</h3><p class="c-bibliographic-information__citation">Whitney, K., Song, WM., Sharma, A. <i>et al.</i> Single-cell transcriptomic and neuropathologic analysis reveals dysregulation of the integrated stress response in progressive supranuclear palsy. <i>Acta Neuropathol</i> <b>148</b>, 80 (2024). https://doi.org/10.1007/s00401-024-02823-w</p><p class="c-bibliographic-information__download-citation u-hide-print"><a data-test="citation-link" data-track="click" data-track-action="download article citation" data-track-label="link" data-track-external="" rel="nofollow" href="https://citation-needed.springer.com/v2/references/10.1007/s00401-024-02823-w?format=refman&flavour=citation">Download citation<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-download-medium"></use></svg></a></p><ul class="c-bibliographic-information__list" 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