{"id":107832,"date":"2024-09-28T07:14:50","date_gmt":"2024-09-28T00:14:50","guid":{"rendered":"https:\/\/hotvideos24.online\/?p=107832"},"modified":"2024-09-28T07:14:50","modified_gmt":"2024-09-28T00:14:50","slug":"huntingtons-protein-mutation-blocks-dna-repair","status":"publish","type":"post","link":"https:\/\/hotvideos24.online\/?p=107832","title":{"rendered":"Huntington\u2019s Protein Mutation Blocks DNA Repair"},"content":{"rendered":"<p> <script async src=\"https:\/\/pagead2.googlesyndication.com\/pagead\/js\/adsbygoogle.js?client=ca-pub-3711241968723425\"\r\n     crossorigin=\"anonymous\"><\/script>\r\n<ins class=\"adsbygoogle\"\r\n     style=\"display:block\"\r\n     data-ad-format=\"fluid\"\r\n     data-ad-layout-key=\"-fb+5w+4e-db+86\"\r\n     data-ad-client=\"ca-pub-3711241968723425\"\r\n     data-ad-slot=\"7910942971\"><\/ins>\r\n<script>\r\n     (adsbygoogle = window.adsbygoogle || []).push({});\r\n<\/script><br \/>\n<\/p>\n<div>\n<p><strong>Summary: <\/strong>Researchers have discovered that the protein mutated in Huntington\u2019s Disease fails to properly repair DNA, leading to reduced brain cell healing. The huntingtin protein normally stimulates the production of PAR molecules, which gather around damaged DNA to facilitate repair.<\/p>\n<p>In Huntington\u2019s patients, the mutated protein does not trigger this process effectively, leading to less efficient DNA repair. This finding could also explain why Huntington\u2019s carriers have lower cancer rates, and it opens new avenues for using PARP inhibitors, typically used in cancer treatment, to explore potential therapies.<\/p>\n<p><strong>Key Facts<\/strong>:<\/p>\n<ul class=\"wp-block-list\">\n<li>Mutated huntingtin protein fails to stimulate DNA repair, leading to brain damage.<\/li>\n<li>Huntington\u2019s carriers show lower rates of cancer, possibly due to this mutation.<\/li>\n<li>Future research may explore using PARP inhibitors as therapies for neurodegenerative diseases.<\/li>\n<\/ul>\n<p><strong>Source: <\/strong>McMaster University<\/p>\n<p><strong>Researchers with McMaster University have discovered that the protein mutated in patients with Huntington\u2019s Disease doesn\u2019t repair DNA as intended, impacting the ability of brain cells to heal themselves. \u00a0\u00a0<\/strong><\/p>\n<p>The research, published in\u00a0<em>PNAS<\/em>\u00a0on Sept. 27, 2024, found that the huntingtin protein helps create special molecules that are important for fixing DNA damage. These molecules, known as Poly [ADP-ribose] (PAR), gather around damaged DNA and, like a net, pull in all the factors needed for the repair process.<\/p>\n<figure class=\"wp-block-image size-full\"><picture fetchpriority=\"high\" decoding=\"async\" class=\"wp-image-104811\"><source type=\"image\/webp\" srcset=\"https:\/\/neurosciencenews.com\/files\/2024\/09\/huntingtin-par-genetics-neuroscience.jpg.webp 1200w, https:\/\/neurosciencenews.com\/files\/2024\/09\/huntingtin-par-genetics-neuroscience-300x200.jpg.webp 300w, https:\/\/neurosciencenews.com\/files\/2024\/09\/huntingtin-par-genetics-neuroscience-770x513.jpg.webp 770w, https:\/\/neurosciencenews.com\/files\/2024\/09\/huntingtin-par-genetics-neuroscience-1155x770.jpg.webp 1155w, https:\/\/neurosciencenews.com\/files\/2024\/09\/huntingtin-par-genetics-neuroscience-370x247.jpg.webp 370w, https:\/\/neurosciencenews.com\/files\/2024\/09\/huntingtin-par-genetics-neuroscience-293x195.jpg.webp 293w, https:\/\/neurosciencenews.com\/files\/2024\/09\/huntingtin-par-genetics-neuroscience-150x100.jpg.webp 150w\" sizes=\"(max-width: 1200px) 100vw, 1200px\"\/><img fetchpriority=\"high\" decoding=\"async\" width=\"1200\" height=\"800\" src=\"https:\/\/neurosciencenews.com\/files\/2024\/09\/huntingtin-par-genetics-neuroscience.jpg\" alt=\"This shows broken DNA.\" srcset=\"https:\/\/neurosciencenews.com\/files\/2024\/09\/huntingtin-par-genetics-neuroscience.jpg 1200w, https:\/\/neurosciencenews.com\/files\/2024\/09\/huntingtin-par-genetics-neuroscience-300x200.jpg 300w, https:\/\/neurosciencenews.com\/files\/2024\/09\/huntingtin-par-genetics-neuroscience-770x513.jpg 770w, https:\/\/neurosciencenews.com\/files\/2024\/09\/huntingtin-par-genetics-neuroscience-1155x770.jpg 1155w, https:\/\/neurosciencenews.com\/files\/2024\/09\/huntingtin-par-genetics-neuroscience-370x247.jpg 370w, https:\/\/neurosciencenews.com\/files\/2024\/09\/huntingtin-par-genetics-neuroscience-293x195.jpg 293w, https:\/\/neurosciencenews.com\/files\/2024\/09\/huntingtin-par-genetics-neuroscience-150x100.jpg 150w\" sizes=\"(max-width: 1200px) 100vw, 1200px\"\/> <\/picture><figcaption class=\"wp-element-caption\">Researchers say future studies should look at different classes of FDA-approved PARP1 inhibitor drugs as they may hold promise not just for Huntington\u2019s Disease but neurodegenerative diseases at large. Credit: Neuroscience News<\/figcaption><\/figure>\n<p>In people with Huntington\u2019s Disease, however, the research found that the mutated version of this protein doesn\u2019t function properly and isn\u2019t capable of stimulating PAR production, ultimately resulting in less effective DNA repair.<\/p>\n<p>The study builds off a discovery researchers with McMaster\u2019s Truant Lab\u00a0published in 2018, which first detailed the huntingtin protein\u2019s involvement in DNA repair.<\/p>\n<p>\u201cWe looked at the PAR levels in the spinal fluid from Huntington\u2019s Disease patients and expected it would be higher due to the higher levels of DNA damage, but we actually found the opposite,\u201d says lead author and McMaster research associate Tamara Maiuri.<\/p>\n<p>\u201cThe levels were quite a bit lower and not only in Huntington\u2019s Disease samples, but also in people who carry the gene but aren\u2019t yet showing outward symptoms.\u201d<\/p>\n<p>This was an unexpected discovery because researchers have previously found PAR levels to be elevated in patients with other neurodegenerative disorders like Parkinson\u2019s and Amyotrophic lateral sclerosis (ALS).<\/p>\n<p>Huntington\u2019s Disease is a genetic disorder that affects the brain and causes the gradual deterioration of nerve cells. For children of parents who have Huntington\u2019s Disease, there\u2019s a 50 per cent chance they will inherit the gene.<\/p>\n<p><strong>Future study on Huntington\u2019s and cancer research<\/strong><\/p>\n<p>This discovery has a unique connection with cancer research.\u00a0Ray Truant, senior author of the study and professor with McMaster\u2019s Department of Biochemistry and Biomedical Sciences, says there are drugs that stop PAR production called PARP inhibitors that are used as cancer treatments.<\/p>\n<p>Truant says this may explain a long-standing observation that carriers of the Huntington\u2019s Disease gene have significantly lower rates of cancer and may confer an evolutionary advantage in the human population, by avoiding early life cancer.<\/p>\n<p>\u201cOne implication is that new huntingtin-level lowering drugs already in clinical trials may have utility outside of Huntington\u2019s Disease to cancer. Based off the findings in this paper, we are working in collaboration with Sheila Singh\u2019s lab at McMaster University\u2019s\u00a0Centre for Discovery in Cancer Research\u00a0to investigate the potential further,\u201d Truant says.<\/p>\n<p>Researchers say future studies should look at different classes of FDA-approved PARP1 inhibitor drugs as they may hold promise not just for Huntington\u2019s Disease but neurodegenerative diseases at large.<\/p>\n<p>Researchers with University College London, Johns Hopkins University and the University of Toronto assisted with this study. The new\u00a0McMaster Center for Advanced Light Microscopy\u00a0was also utilized to image the huntingtin protein with PAR chains, giving researchers a closer look at how these molecules interact. This was done with the assistance of McMaster\u2019s Andres Lab.<\/p>\n<p><strong>Funding: <\/strong>This research was supported by the Canadian Institutes of Health Research Project Grant and the Krembil Foundation, the Huntington Disease Society of America Berman Topper Career Development Fellowship and HD Human Biology Project.<\/p>\n<h2 class=\"wp-block-heading\">About this genetics and Huntington\u2019s disease research news<\/h2>\n<p class=\"has-background\" style=\"background-color:#ffffe8\"><strong>Author: <\/strong><a href=\"http:\/\/neurosciencenews.com\/cdn-cgi\/l\/email-protection#87f4f3f5e6e9edb3c7eae4eae6f4f3e2f5a9e4e6\" target=\"_blank\" rel=\"noreferrer noopener\">Jennifer Stranges<\/a><br \/><strong>Source: <\/strong><a href=\"https:\/\/mcmaster.ca\" target=\"_blank\" rel=\"noreferrer noopener\">McMaster University<\/a><br \/><strong>Contact: <\/strong>Jennifer Stranges \u2013 McMaster University<br \/><strong>Image: <\/strong>The image is credited to Neuroscience News<\/p>\n<p class=\"has-background\" style=\"background-color:#ffffe8\"><strong>Original Research: <\/strong>Closed access.<br \/>\u201c<a href=\"https:\/\/www.pnas.org\/doi\/10.1073\/pnas.2318098121\" target=\"_blank\" rel=\"noreferrer noopener\">Poly ADP-ribose signaling is dysregulated in Huntington disease<\/a>\u201d by Tamara Maiuri et al. <em>PNAS<\/em><\/p>\n<hr class=\"wp-block-separator has-text-color has-pale-cyan-blue-color has-alpha-channel-opacity has-pale-cyan-blue-background-color has-background\"\/>\n<p><strong>Abstract<\/strong><\/p>\n<p><strong>Poly ADP-ribose signaling is dysregulated in Huntington disease<\/strong><\/p>\n<p>Huntington disease (HD) is a genetic neurodegenerative disease caused by cytosine, adenine, guanine (CAG) expansion in the\u00a0<em>Huntingtin<\/em>\u00a0(<em>HTT<\/em>) gene, translating to an expanded polyglutamine tract in the HTT protein.<\/p>\n<p>Age at disease onset correlates to CAG repeat length but varies by decades between individuals with identical repeat lengths. Genome-wide association studies link HD modification to DNA repair and mitochondrial health pathways.<\/p>\n<p>Clinical studies show elevated DNA damage in HD, even at the premanifest stage. A major DNA repair node influencing neurodegenerative disease is the PARP pathway. Accumulation of poly adenosine diphosphate (ADP)-ribose (PAR) has been implicated in Alzheimer and Parkinson diseases, as well as cerebellar ataxia.<\/p>\n<p>We report that HD mutation carriers have lower cerebrospinal fluid PAR levels than healthy controls, starting at the premanifest stage. Human HD induced pluripotent stem cell-derived neurons and patient-derived fibroblasts have diminished PAR response in the context of elevated DNA damage.<\/p>\n<p>We have defined a PAR-binding motif in HTT, detected HTT complexed with PARylated proteins in human cells during stress, and localized HTT to mitotic chromosomes upon inhibition of PAR degradation. Direct HTT PAR binding was measured by fluorescence polarization and visualized by atomic force microscopy at the single molecule level.<\/p>\n<p>While wild-type and mutant HTT did not differ in their PAR binding ability, purified wild-type HTT protein increased in vitro PARP1 activity while mutant HTT did not.<\/p>\n<p>These results provide insight into an early molecular mechanism of HD, suggesting possible targets for the design of early preventive therapies.<\/p>\n<p> <!-- Form created by Optin Forms plugin by WPKube: create beautiful optin forms with ease! --> <!-- https:\/\/wpkube.com\/ --><!--optinforms-form5-container--> <!-- \/ Optin Forms --> <\/div>\n<p><script async src=\"https:\/\/pagead2.googlesyndication.com\/pagead\/js\/adsbygoogle.js?client=ca-pub-3711241968723425\"\r\n     crossorigin=\"anonymous\"><\/script>\r\n<ins class=\"adsbygoogle\"\r\n     style=\"display:block\"\r\n     data-ad-format=\"fluid\"\r\n     data-ad-layout-key=\"-fb+5w+4e-db+86\"\r\n     data-ad-client=\"ca-pub-3711241968723425\"\r\n     data-ad-slot=\"7910942971\"><\/ins>\r\n<script>\r\n     (adsbygoogle = window.adsbygoogle || []).push({});\r\n<\/script><br \/>\n<br \/><div data-type=\"_mgwidget\" data-widget-id=\"1660802\">\r\n<\/div>\r\n<script>(function(w,q){w[q]=w[q]||[];w[q].push([\"_mgc.load\"])})(window,\"_mgq\");\r\n<\/script>\r\n<br \/>\n<br \/><a href=\"https:\/\/neurosciencenews.com\/huntingtin-par-genetics-27713\/\">Source link <\/a><\/p>\n","protected":false},"excerpt":{"rendered":"<p>Summary: Researchers have discovered that the protein mutated in Huntington\u2019s Disease fails to properly repair DNA, leading to reduced brain cell healing. The huntingtin protein normally stimulates the production of &hellip; <a href=\"https:\/\/hotvideos24.online\/?p=107832\" class=\"more-link\">Read More<\/a><\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[8628],"tags":[],"class_list":["post-107832","post","type-post","status-publish","format-standard","hentry","category-science","entry"],"_links":{"self":[{"href":"https:\/\/hotvideos24.online\/index.php?rest_route=\/wp\/v2\/posts\/107832","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/hotvideos24.online\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/hotvideos24.online\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/hotvideos24.online\/index.php?rest_route=\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/hotvideos24.online\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=107832"}],"version-history":[{"count":0,"href":"https:\/\/hotvideos24.online\/index.php?rest_route=\/wp\/v2\/posts\/107832\/revisions"}],"wp:attachment":[{"href":"https:\/\/hotvideos24.online\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=107832"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/hotvideos24.online\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=107832"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/hotvideos24.online\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=107832"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}