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<h2 class="element-invisible">You are here</h2><div class="breadcrumb"><a href="/">Home</a> » <a href="/news-events">News & Events</a> » <a href="/news-events/nih-research-matters">NIH Research Matters</a></div> <div class="l-region l-region--section-header">
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<p class="publishdate"><span property="dc:date" datatype="xsd:dateTime" content="2023-03-07T00:00:00-05:00" class="date-display-single">March 7, 2023</span></p><div class='syndicate'><h1>Identifying potential treatments for ALS</h1><div class="callout callout-with-border"><h3>At a Glance</h3>
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<ul>
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<li>Researchers identified two different proteins that, when suppressed, reduced the neuronal damage caused by ALS.</li>
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<li>The experimental results suggest it may be possible to develop treatments that work broadly in different types of ALS.</li>
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</ul></div><div class="media-float-right"><div class="ds-1col file file-image file-image-jpeg view-mode-floated_media clearfix">
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<picture title="Human induced motor neurons">
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<!--[if IE 9]><video style="display: none;"><![endif]-->
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-large/public/news-events/research-matters/2023/20230307-neurons.jpg?itok=MI8U_2-4&timestamp=1678196579 1x" media="screen and (min-width: 960px)" />
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-medium/public/news-events/research-matters/2023/20230307-neurons.jpg?itok=JGz8F7lo&timestamp=1678196579 1x" media="screen and (min-width: 800px)" />
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-medium-small/public/news-events/research-matters/2023/20230307-neurons.jpg?itok=DdSZF8NT&timestamp=1678196579 1x" media="screen and (min-width: 600px)" />
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-small/public/news-events/research-matters/2023/20230307-neurons.jpg?itok=LYx3YNy4&timestamp=1678196579 1x" media="screen and (min-width: 480px)" />
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<source srcset="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-tiny/public/news-events/research-matters/2023/20230307-neurons.jpg?itok=i-EWKR3o&timestamp=1678196579 1x" media="screen and (min-width: 0)" />
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<!--[if IE 9]></video><![endif]-->
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<img src="https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-medium/public/news-events/research-matters/2023/20230307-neurons.jpg?itok=JGz8F7lo&timestamp=1678196579" alt="Human induced motor neurons." title="Human induced motor neurons" />
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</picture><span class="caption">Human induced motor neurons. Neurons are labelled with purple, with a green fluorescent label marking their nuclei.</span><span class="credit">Ichida Lab</span></div>
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</div><p>Amyotrophic lateral sclerosis, or ALS, is a rare but devastating neurological disease. In ALS, misfolded proteins build up within motor neurons—the nerve cells in the brain and spinal cord that control voluntary muscle movement. The inability to clear this toxic protein buildup leads to muscle weakness, paralysis, and eventually death.</p>
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<p>Some cases of ALS are caused by known, inherited genetic mutations. But most are from sporadic, unknown causes. Rather than target each genetic cause of ALS, researchers have been seeking treatments that could be used across different types. An NIH-funded research team led by Dr. Justin Ichida from the University of Southern California has been searching for cellular processes that could be manipulated to treat ALS regardless of the genetic drivers of a person’s disease.</p>
|
||
|
||
<p>The first of two new studies from the team was published in <em>Cell</em> on February 16, 2023. In earlier work, they found that compounds that blocked a protein called PIKFYVE kinase extended the lives of ALS motor neurons. One of these compounds was a small molecule called apilimod.</p>
|
||
|
||
<p>In their follow-up study, the team tested apilimod in motor neurons with many different drivers of ALS. They also used several genetic methods to shut down PIKFYVE. All methods of PIKFYVE inhibition extended the lives of the various ALS neuron types tested.</p>
|
||
|
||
<p>Further work teased out the cellular mechanisms responsible for this protective effect. The researchers found that inhibiting PIKFYVE helped neurons clear misfolded, toxic proteins. This happened because a waste-removal process called exocytosis became activated when PIKFYVE was shut down.</p>
|
||
|
||
<p>The toxic version of a protein called TDP-43 has been linked to ALS and other neurodegenerative diseases. This protein was effectively cleared from the cells through exocytosis after PIKFYVE was inhibited.</p>
|
||
|
||
<p>When the researchers blocked PIKFYVE in several animal models of ALS—including mice with a misfolded version of TDP-43—motor function was improved, and the animals lived longer.</p>
|
||
|
||
<p>The team’s second study was published on February 2, 2023, in <em>Cell Stem Cell</em>. In that work, the researchers screened a library of almost 2,000 approved drugs and other compounds for their ability to extend the life of ALS motor neurons. They found that some of the most promising compounds altered cellular signaling driven by hormones called androgens (such as testosterone) in the body.</p>
|
||
|
||
<p>The long-term manipulation of such hormones may have unwanted side effects. So, the researchers searched for other targets that altered gene activity levels in similar ways in motor neurons. Their top candidate was called SFY2.</p>
|
||
|
||
<p>The team found that suppressing SYF2 levels using genetic techniques increased survival in most types of ALS motor neurons tested, including those that accumulate toxic TDP-43.</p>
|
||
|
||
<p>In mice, suppressing SYF2 changed the way TDP-43 was exported from the nuclei of cells. This stopped the buildup of toxic protein clumps within neurons. Reducing the amount of SYF2 in the mice improved motor functioning as well.</p>
|
||
|
||
<p>“Our discoveries bring us closer to achieving our big picture goal: finding treatments that can be broadly effective for all patients who suffer from ALS,” Ichida says.</p>
|
||
|
||
<p>Before these approaches could be tested in people, future work will be needed to identify the safest ways to suppress such cellular pathways.</p>
|
||
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||
<p>—by Sharon Reynolds</p></div><h2 class="label-above">Related Links</h2><ul class="spaced print-urls"><li><a href="https://www.nih.gov/news-events/nih-research-matters/links-found-between-viruses-neurodegenerative-diseases" target="_top">Links Found between Viruses and Neurodegenerative Diseases</a></li><li><a href="https://www.nih.gov/news-events/nih-research-matters/how-proteins-connect-common-neurodegenerative-diseases" target="_top">How Proteins Connect Common Neurodegenerative Diseases</a></li><li><a href="https://www.nih.gov/news-events/nih-research-matters/cellular-defect-found-inherited-sporadic-als" target="_top">Cellular Defect Found in Inherited and Sporadic ALS</a></li><li><a href="https://www.nih.gov/news-events/nih-research-matters/als-related-mutations-prevent-rna-transport-nerves" target="_top">ALS-Related Mutations Prevent RNA Transport in Nerves</a></li><li><a href="https://www.nih.gov/news-events/nih-research-matters/biomarker-tracking-progression-als" target="_top">A Biomarker for Tracking the Progression of ALS</a></li><li><a href="https://www.nih.gov/news-events/nih-research-matters/dormant-viral-genes-may-awaken-cause-als" target="_top">Dormant Viral Genes May Awaken to Cause ALS</a></li><li><a href="https://www.nih.gov/news-events/nih-research-matters/nuclear-pore-problems-may-lead-als-dementia" target="_top">Nuclear Pore Problems May Lead to ALS and Dementia</a></li><li><a href="https://newsinhealth.nih.gov/2015/08/all-about-als" target="_top">All About ALS: Understanding a Devastating Disorder</a></li><li><a href="https://www.ninds.nih.gov/health-information/disorders/amyotrophic-lateral-sclerosis-als" target="_top">Amyotrophic Lateral Sclerosis (ALS)</a></li></ul><p class="footnote"><strong class="label-inline">References: </strong><a href="https://pubmed.ncbi.nlm.nih.gov/36754049/">PIKFYVE inhibition mitigates disease in models of diverse forms of ALS.</a> Hung ST, Linares GR, Chang WH, Eoh Y, Krishnan G, Mendonca S, Hong S, Shi Y, Santana M, Kueth C, Macklin-Isquierdo S, Perry S, Duhaime S, Maios C, Chang J, Perez J, Couto A, Lai J, Li Y, Alworth SV, Hendricks E, Wang Y, Zlokovic BV, Dickman DK, Parker JA, Zarnescu DC, Gao FB, Ichida JK. <em>Cell</em>. 2023 Feb 16;186(4):786-802.e28. doi: 10.1016/j.cell.2023.01.005. Epub 2023 Feb 7. PMID: 36754049.<br />
|
||
<br />
|
||
<a href="https://pubmed.ncbi.nlm.nih.gov/36736291/"><em>SYF2</em> suppression mitigates neurodegeneration in models of diverse forms of ALS.</a> Linares GR, Li Y, Chang WH, Rubin-Sigler J, Mendonca S, Hong S, Eoh Y, Guo W, Huang YH, Chang J, Tu S, Dorjsuren N, Santana M, Hung ST, Yu J, Perez J, Chickering M, Cheng TY, Huang CC, Lee SJ, Deng HJ, Bach KT, Gray K, Subramanyam V, Rosenfeld J, Alworth SV, Goodarzi H, Ichida JK. <em>Cell Stem Cell</em>. 2023 Feb 2;30(2):171-187.e14. doi: 10.1016/j.stem.2023.01.005.PMID: 36736291.</p><p class="footnote"><strong class="label-inline">Funding: </strong>NIH’s National Institute of Neurological Disorders and Stroke (NINDS); US Department of Defense; Donald E. and Delia B. Baxter Foundation; Tau Consortium; Ford Foundation; Muscular Dystrophy Association; New York Stem Cell Foundation; Alzheimer's Drug Discovery Foundation; Association for Frontotemporal Degeneration; Pape Adams Foundation; John Douglas French Alzheimer's Foundation; Harrington Discovery Institute; Milken Family Foundation; USC Broad Innovation Award; Southern California Clinical and Translational Science Institute; Keck Medicine of USC; Target ALS Foundation; John Douglas French Alzheimer’s Foundation; Broad Institute; ALS Association; Lawrence and Isabel Barnett Drug Development Award; Frick Foundation for ALS Research; University of Southern California Alzheimer′s Disease Research Center; California Institute for Regenerative Medicine.</p>
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