CINXE.COM

<!DOCTYPE html>      <html lang='en' class='no-js'>  <head> <meta charset='utf-8'> <meta content='text/html; charset=UTF-8' http-equiv='Content-Type'> <meta content='The Journal of Clinical Investigation' name='AUTHOR'>  <meta content='width=device-width, initial-scale=1.0' name='viewport'> <link href='/rss' rel='alternate' title='JCI New Article RSS' type='application/rss+xml'> <meta name="csrf-param" content="authenticity_token" /> <meta name="csrf-token" content="1za7KOedpaSTLCEiFZt0p+xSDZQQ8vwh0m/CBW8FoWGl+H++btJe8vN4OPkIMp2kSSUxSBW44frOC2jiQExjdg==" /> <link rel="shortcut icon" type="image/x-icon" href="/assets/jci-favicon-378ea4dd43f03bc78136c6a261d9b28f6811fe59d12db426eae78cf0691b0008.ico" /> <title> JCI - Welcome </title> <link rel="stylesheet" media="all" href="/assets/application-4e3473ed7442aa1dc35d11f58ed4edfbd690fa57a3eb3a1daca0cd68dc7fb1e0.css" />  <style> @font-face { font-family: "klavika-bold"; src: url("///var/www/jci/jci/releases/20250410184254/vendor/common/fonts/klavika/eot/KlavikaWebBasicBold.eot") format('eot'), src: url("///var/www/jci/jci/releases/20250410184254/vendor/common/fonts/klavika/eot/KlavikaWebBasicBold.eot?#iefix") format("embedded-opentype"), url("///var/www/jci/jci/releases/20250410184254/vendor/common/fonts/klavika/woff/KlavikaWebBasicBold.woff") format("woff") } </style> <script> //Google Tag Manager Data Layer //Values must be set before GTM tags are triggered window.dataLayer = window.dataLayer || []; window.dataLayer.push({ 'siteName': 'content-jci', 'ipAddress': '8.222.208.146', 'environment': 'production', }); </script> <script src="/assets/vendor/modernizr-2f68aa04c7424c280c5bc9db8b68f7f6ff70bcd38254c5b89383eac8e89b1781.js"></script> <script type='text/javascript'> var googletag = googletag || {}; googletag.cmd = googletag.cmd || []; (function () { var gads = document.createElement('script'); gads.async = true; gads.type = 'text/javascript'; var useSSL = 'https:' == document.location.protocol; gads.src = (useSSL ? 'https:' : 'http:') + '//www.googletagservices.com/tag/js/gpt.js'; var node = document.getElementsByTagName('script')[0]; node.parentNode.insertBefore(gads, node); })(); googletag.cmd.push(function () { // NOTE: This script manages google ads, more info at doc/GoogleAds.md var mapping = googletag.sizeMapping().addSize([800, 600], [300, 250]).addSize([640, 480], [260, 217]).build(); var mapping2 = googletag.sizeMapping() .addSize([1920, 1080], [728, 90])//All desktop like resolutions are set to 728x90 .addSize([800, 600], [728, 90]) .addSize([640, 480], [728, 90]) .addSize([0, 0], [320, 50]) //Smaller than 640x480 screens .build(); googletag.defineSlot('/82117132/jci-homepage-med-rectangle-left-col-top', [[300, 250],[260, 217]], 'jci-homepage-med-rectangle-left-col-top').defineSizeMapping(mapping).addService(googletag.pubads()); googletag.defineSlot('/82117132/jci-article-interior-leaderboard-top', [[728, 90],[320, 50]], 'jci-article-interior-leaderboard-top').defineSizeMapping(mapping2).addService(googletag.pubads()); googletag.defineSlot('/82117132/jci-article-interior-leaderboard-bottom', [728, 90], 'jci-article-interior-leaderboard-bottom').addService(googletag.pubads()); googletag.defineSlot('/82117132/jci-article-interior-skyscraper-right-col', [160, 600], 'jci-article-interior-skyscraper-right-col').addService(googletag.pubads()); googletag.defineSlot('/82117132/jci-interior-skyscraper-right-col', [160, 600], 'jci-interior-skyscraper-right-col').addService(googletag.pubads()); // collapseEmptyDivs requires all slots be defined above. googletag.pubads().collapseEmptyDivs(true); googletag.enableServices(); }); </script> </head> <body class='' id='posts_controller'> <div class='off-canvas-wrap' data-offcanvas=''> <div class='inner-wrap'> <div class='fixed show-for-large-up'> <div class='row menu-align' id='logo-bar'> <div class='small-12 columns'> <div class='cross-journal-container'> Go to <a href='http://insight.jci.org'>JCI Insight</a> </div> <a href="/"><img src="/assets/common/jci-spelled-out-white-on-transparent.20160208-958617d51a205b239bcef41eae5703962aee0ae2fcc9fbda0237e635a09ac7f3.png" /></a> </div> </div> <div class='row menu-align' id='journal-bar'> <div class='small-12 columns'> <ul class='inline-list'> <li><a href="/kiosks/about">About</a></li> <li><a href="/kiosks/editorial-board">Editors</a></li> <li><a href="/kiosks/about/consulting-editors">Consulting Editors</a></li> <li><a href="/kiosks/authors">For authors</a></li> <li><a href="/kiosks/ethics">Publication ethics</a></li> <li><a href="/kiosks/connect">Publication alerts by email</a></li> <li><a href="/kiosks/advertise">Advertising</a></li> <li><a href="https://the-asci.org/controllers/asci/JobBoard.php">Job board</a></li> <li><a href="/kiosks/contact">Contact</a></li> </ul> </div> </div> <div id='content-bar'> <nav class='top-bar' data-topbar=''> <section class='top-bar-section'> <ul class='left'> <li class='not-click'> <a href="/tags/141">Clinical Research and Public Health</a> </li> <li class='not-click'> <a id="topmenu_current_issue" href="/current">Current issue</a> </li> <li class='not-click'> <a href="/archive">Past issues</a> </li> <li class='has-dropdown not-click'> <a>By specialty</a> <ul class='dropdown'> <li><a href="/tags/118">COVID-19</a></li> <li><a href="/tags/15">Cardiology</a></li> <li><a href="/tags/21">Gastroenterology</a></li> <li><a href="/tags/25">Immunology</a></li> <li><a href="/tags/28">Metabolism</a></li> <li><a href="/tags/31">Nephrology</a></li> <li><a href="/tags/32">Neuroscience</a></li> <li><a href="/tags/33">Oncology</a></li> <li><a href="/tags/36">Pulmonology</a></li> <li><a href="/tags/42">Vascular biology</a></li> <li><a href="/specialties">All ...</a></li> </ul> </li> <li class='has-dropdown not-click'> <a href="/videos">Videos</a> <ul class='dropdown'> <li><a href="/videos/cgms">Conversations with Giants in Medicine</a></li> <li><a href="/videos/video_abstracts">Video Abstracts</a></li> </ul> </li> <li class='has-dropdown not-click'> <a href="/tags/reviews">Reviews</a> <ul class='dropdown'> <li> <label>Reviews</label> </li> <li><a href="/tags/reviews">View all reviews ...</a></li> <li class='divider'></li> <li> <label>Review Series</label> </li> <li><a href="/review_series/131">Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)</a></li> <li><a href="/review_series/130">Microbiome in Health and Disease (Feb 2025)</a></li> <li><a href="/review_series/127">Substance Use Disorders (Oct 2024)</a></li> <li><a href="/review_series/128">Clonal Hematopoiesis (Oct 2024)</a></li> <li><a href="/review_series/129">Sex Differences in Medicine (Sep 2024)</a></li> <li><a href="/review_series/126">Vascular Malformations (Apr 2024)</a></li> <li><a href="/review_series/125">Lung inflammatory injury and tissue repair (Jul 2023)</a></li> <li> <a href="/review_series">View all review series ...</a> </li> </ul> </li> <li class='not-click'> <a href="/tags/111">Viewpoint</a> </li> <li class='has-dropdown not-click'> <a>Collections</a> <ul class='dropdown'> <li><a href="/in-press-preview">In-Press Preview</a></li> <li><a href="/tags/141">Clinical Research and Public Health</a></li> <li><a href="/tags/127">Research Letters</a></li> <li><a href="/tags/75">Letters to the Editor</a></li> <li><a href="/tags/56">Editorials</a></li> <li><a href="/tags/44">Commentaries</a></li> <li><a href="/tags/123">Editor's notes</a></li> <li><a href="/tags/2">Reviews</a></li> <li><a href="/tags/111">Viewpoints</a></li> <li><a href="/collections/topic/jci-100th-anniversary">100th anniversary</a></li> <li><a href="/top_articles">Top read articles</a></li> </ul> </li> </ul> <ul class='right'> <li class='has-form'> <div id='search-area'> <form action="/search/results" accept-charset="UTF-8" method="get"> <input type="text" name="q" id="q" value="" placeholder="Search the JCI" /> <input type="image" src="/assets/search-black-ba9b554d6f74b1c93d6e6ab71d1c9830c18a20fc6b7e72393f136f5d875141ac.png" value="" /> </form> </div> </li> </ul> </section> </nav> </div> </div> <nav class='tab-bar hide-for-large-up fixed' id='small-navbar'> <section class='left-small'> <a class='left-off-canvas-toggle menu-icon'> <span></span> </a> </section> <section class='middle tab-bar-section'> <h1 class='title'><a href="/"><img width="40" src="/assets/common/jci-only-white-6c989e8f9744a714482158b82319d50aa8437aa4c8524c4f3dcf8450299cd4b7.png" /></a></h1> </section> </nav> <aside class='left-off-canvas-menu'> <ul class='off-canvas-list'> <li> <label>The Journal of Clinical Investigation</label> </li> <li><form action="/search/results" accept-charset="UTF-8" method="get"> <div class='row collapse' id='search-div-offcanvas'> <div class='small-8 columns'> <input name='q' placeholder='Search the JCI' type='text'> </div> <div class='small-4 columns'> <input type="image" src="/assets/common/search-white-530f3f95b9080d73eba51eaeffdf1a3922af42ccc277a2d1d987b8aa24423c96.png" id="search-icon-offcanvas" /> </div> </div> </form> </li> <li><a id="offcanvas_current_issue" href="/current">Current issue</a></li> <li><a href="/archive">Past issues</a></li> <li><a href="/specialties">Specialties</a></li> <li><a href="/tags/reviews">Reviews</a></li> <li><a href="/review_series">Review series</a></li> <li> <label>Videos</label> </li> <li><a href="/videos/cgms">Conversations with Giants in Medicine</a></li> <li><a href="/videos/video_abstracts">Video Abstracts</a></li> <li> <label>Collections</label> </li> <li><a href="/in-press-preview">In-Press Preview</a></li> <li><a href="/tags/141">Clinical Research and Public Health</a></li> <li><a href="/tags/127">Research Letters</a></li> <li><a href="/tags/75">Letters to the Editor</a></li> <li><a href="/tags/56">Editorials</a></li> <li><a href="/tags/44">Commentaries</a></li> <li><a href="/tags/123">Editor's notes</a></li> <li><a href="/tags/2">Reviews</a></li> <li><a href="/tags/111">Viewpoints</a></li> <li><a href="/collections/topic/jci-100th-anniversary">100th anniversary</a></li> <li><a href="/top_articles">Top read articles</a></li> <li> <label>Journal Details</label> </li> <li><a href="/kiosks/about">About</a></li> <li><a href="/kiosks/editorial-board">Editors</a></li> <li><a href="/kiosks/about/consulting-editors">Consulting Editors</a></li> <li><a href="/kiosks/authors">For authors</a></li> <li><a href="/kiosks/ethics">Publication ethics</a></li> <li><a href="/kiosks/connect">Publication alerts by email</a></li> <li><a href="/kiosks/advertise">Advertising</a></li> <li><a href="https://the-asci.org/controllers/asci/JobBoard.php">Job board</a></li> <li><a href="/kiosks/contact">Contact</a></li> </ul> </aside> <a class='exit-off-canvas'></a>  <div class='row content-wrapper'> <div class='small-12 columns'> <div class='menu-align'> <div class='row'> <div class='large-10 medium-9 small-12 columns'> <div class='row'> <div class='small-12 columns'> <h1>Synergy among Parkinson’s disease-associated genes</h1> </div> </div> <div class='row'> <div class='small-12 columns'> </div> </div> <div class='row'> <div class='small-12 columns'> <p><p><img src="https://dm5migu4zj3pb.cloudfront.net/posts/file/355/79300.jpg" /></p> <p>Degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) is a hallmark of Parkinson’s disease (PD). While the molecular mechanisms that guide the selective loss of these cells are not fully understood, several factors, including mitochondrial dysfunction, oxidative stress, and diminished neurotrophic signaling, have been implicated. Durga Meka and colleagues at the University Medical Center Hamburg-Eppendorf evaluated DA neuron survival and mitochondrial integrity following loss of parkin and/or the receptor for glial cell line-derived neurotrophic factor (GDNF) RET, both of which have been independently implicated in PD. Mice lacking parkin alone showed no age-dependent loss of DA neurons; however, deletion of parkin in combination with <em>Ret</em> exacerbated the progressive degeneration of SNpc DA neurons observed in RET-deficient animals. Conversely, overexpression of parkin rescued the neurodegenerative phenotype in RET-deficient mice. In a neuronal cell line, knock down of either parkin or RET resulted in mitochondrial fragmentation, which could be rescued by restoration of GDNF signaling or parkin, respectively. Moreover, PI3K-dependent activation of NF<strong>-</strong>κB was critical for the restoration of mitochondrial integrity. Collectively, these findings identify a synergistic role for RET and parkin in SNpc DA neuron survival and mitochondrial integrity. The accompanying image shows DA neurons (stained with anti-tyrosine hydroxylase, brown) in the SNpc (outlined in red) and ventral tegmental area (outlined in blue) of 24-month old control (upper left), parkin KO (upper right), RET KO (lower left), and RET/parkin double-KO (lower right) mice.</p> <p> </p> </p> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='published-at'> Published March 30, 2015, by Daniel Albaugh </span> <div> <p><a href="/tags/5"><span style='margin-right: 6px' class="label-article-type">Scientific Show Stopper</span></a><a href="/tags/32"><span style='margin-right: 6px' class="label-specialty">Neuroscience</span></a></p> </div> </div> </div> <div class='row'> <div class='small-12 columns' style='padding-bottom:12px;'> <h3>Related articles</h3> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/79300">Parkin cooperates with GDNF/RET signaling to prevent dopaminergic neuron degeneration</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/79300">Durga Praveen Meka, … , Konstanze F. Winklhofer, Edgar R. Kramer</a> <a class='hide-for-small show-more' data-reveal-id='article33545-more' href='#'> <div class='article-authors'> Durga Praveen Meka, … , Konstanze F. Winklhofer, Edgar R. Kramer </div> </a> <span class='article-published-at'> Published March 30, 2015 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2015;<a id="article_metadata" href="http://www.jci.org/125/5">125(5)</a>:1873-1885. <a href="https://doi.org/10.1172/JCI79300">https://doi.org/10.1172/JCI79300</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/79300">Text</a> | <a href="/articles/view/79300/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <a href="/tags/51"><span class='label-article-type'> Research Article </span> </a><a href="/tags/32"><span class='label-specialty'> Neuroscience </span> </a><span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI79300' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article33545-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/79300">Parkin cooperates with GDNF/RET signaling to prevent dopaminergic neuron degeneration</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/79300">Text</a></li> <li><a class="button tiny" href="/articles/view/79300/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Parkin and the glial cell line–derived neurotrophic factor (GDNF) receptor RET have both been independently linked to the dopaminergic neuron degeneration that underlies Parkinson’s disease (PD). In the present study, we demonstrate that there is genetic crosstalk between parkin and the receptor tyrosine kinase RET in two different mouse models of PD. Mice lacking both parkin and RET exhibited accelerated dopaminergic cell and axonal loss compared with parkin-deficient animals, which showed none, and RET-deficient mice, in which we found moderate degeneration. Transgenic expression of parkin protected the dopaminergic systems of aged RET-deficient mice. Downregulation of either parkin or RET in neuronal cells impaired mitochondrial function and morphology. Parkin expression restored mitochondrial function in GDNF/RET-deficient cells, while GDNF stimulation rescued mitochondrial defects in parkin-deficient cells. In both cases, improved mitochondrial function was the result of activation of the prosurvival NF-κB pathway, which was mediated by RET through the phosphoinositide-3-kinase (PI3K) pathway. Taken together, these observations indicate that parkin and the RET signaling cascade converge to control mitochondrial integrity and thereby properly maintain substantia nigra pars compacta dopaminergic neurons and their innervation in the striatum. The demonstration of crosstalk between parkin and RET highlights the interplay in the protein network that is altered in PD and suggests potential therapeutic targets and strategies to treat PD.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Durga Praveen Meka, Anne Kathrin Müller-Rischart, Prakash Nidadavolu, Behnam Mohammadi, Elisa Motori, Srinivas Kumar Ponna, Helia Aboutalebi, Mahmoud Bassal, Anil Annamneedi, Barbara Finckh, Margit Miesbauer, Natalie Rotermund, Christian Lohr, Jörg Tatzelt, Konstanze F. Winklhofer, Edgar R. Kramer</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> </div> <div class='large-2 medium-3 hide-for-small columns' style='padding: 12px 9px 12px 9px;'> <div style='width:100%; text-align: center;'> <div id='jci-interior-skyscraper-right-col'> <span class='secondary label'>Advertisement</span> <script> try { googletag.cmd.push(function () { googletag.display('jci-interior-skyscraper-right-col'); }); } catch(e){} </script> </div> </div> </div> </div> </div> </div> </div> </div> <div id='footer'> <div class='row panel-padding'> <div class='small-6 columns'> <div id='social-links'> <a onclick="trackOutboundLink('/twitter?ref=footer');" href="/twitter"><img title="Twitter" src="/assets/social/twitter-round-blue-78025a92064e3594e44e4ccf5446aefeafba696cd3c8e4a7be1850c7c9f62aba.png" /></a> <a onclick="trackOutboundLink('/facebook?ref=footer');" href="/facebook"><img title="Facebook" src="/assets/social/facebook-round-blue-2787910d46dcbdbee4bd34030fee044e5a77cfda2221af9191d437b2f5fadeb1.png" /></a> <a href="/rss"><img title="RSS" src="/assets/social/rss-round-color-6f5fa8e93dc066ee4923a36ba6a7cb97d53c5b77de78a2c7b2a721adc603f342.png" /></a> </div> <br> Copyright © 2025 <a href="http://www.the-asci.org">American Society for Clinical Investigation</a> <br> ISSN: 0021-9738 (print), 1558-8238 (online) </div> <div class='small-6 columns'> <div class='row'> <div class='small-12 columns'> <h4 class='notices-signup'>Sign up for email alerts</h4> <form action='https://notices.jci.org/subscribers/new' method='get'> <input name='utm_source' type='hidden' value='jci'> <input name='utm_medium' type='hidden' value='web'> <input name='utm_campaign' type='hidden' value='email_signup'> <input name='utm_content' type='hidden' value='footer'> <div class='row'> <div class='small-12 medium-9 columns'> <input name='email_address' placeholder='Your email address' required type='text'> </div> <div class='small-12 medium-3 columns'> <input class='button tiny orange' type='submit' value='Sign up'> </div> </div> </form> </div> </div> </div> </div> </div> </div> <script src="/assets/application-27f18b5fe3b7302e5b3e3c6d7cf9bb3f54759fad32679209f5aef429b89f3aef.js"></script>  <script src="//s7.addthis.com/js/300/addthis_widget.js#pubid=ra-4d8389db4b0bb592" async="async"></script> <script src="//d1bxh8uas1mnw7.cloudfront.net/assets/embed.js" async="async"></script>  </body> </html>