{"id":16800,"date":"2025-04-13T15:05:08","date_gmt":"2025-04-13T15:05:08","guid":{"rendered":"https:\/\/www.europesays.com\/uk\/16800\/"},"modified":"2025-04-13T15:05:08","modified_gmt":"2025-04-13T15:05:08","slug":"new-genes-linked-to-parkinsons-risk-revealed","status":"publish","type":"post","link":"https:\/\/www.europesays.com\/uk\/16800\/","title":{"rendered":"New Genes Linked to Parkinson\u2019s Risk Revealed"},"content":{"rendered":"<p><strong>Summary: <\/strong>Researchers have long wondered why some people with high-risk Parkinson\u2019s gene variants develop the disease while others don\u2019t. A new study has uncovered that additional genetic players, particularly the Commander gene complex, influence whether the disease manifests.<\/p>\n<p>Using CRISPR interference to screen the entire genome, scientists identified how Commander proteins impact lysosomal function \u2014 a key cellular recycling system tied to Parkinson\u2019s pathology. These findings not only clarify disease mechanisms but also introduce new targets for potential therapies.<\/p>\n<p><strong>Key Facts:<\/strong><\/p>\n<ul class=\"wp-block-list\">\n<li><strong>Commander Genes Identified:<\/strong> A set of 16 Commander proteins helps regulate lysosomal function, influencing Parkinson\u2019s disease development.<\/li>\n<li><strong>CRISPR-Based Screening:<\/strong> Genome-wide CRISPR interference revealed which genes modulate GCase activity and Parkinson\u2019s risk.<\/li>\n<li><strong>New Drug Pathways:<\/strong> Enhancing Commander protein function may offer a therapeutic route to restore lysosomal health and slow neurodegeneration.<\/li>\n<\/ul>\n<p><strong>Source: <\/strong>Northwestern University<\/p>\n<p><strong>A longstanding mystery in Parkinson\u2019s disease research has been why some individuals carrying pathogenic variants that increase their risk of PD go on to develop the disease, while others who also carry such variants do not. The prevailing theory has suggested additional genetic factors may play a role.<\/strong><\/p>\n<p>To address this question, a new study from Northwestern Medicine used modern technology, called CRISPR interference, to systematically examine every gene in the human genome.<\/p>\n<p>  <img fetchpriority=\"high\" decoding=\"async\" width=\"1200\" height=\"799\" src=\"https:\/\/www.europesays.com\/uk\/wp-content\/uploads\/2025\/04\/parkinsons-genetics-crispr-neuroscience.jpg\" alt=\"This shows a brain.\"  \/> Future research will need to determine the extent to which the Commander complex plays a role in other neurodegenerative disorders that exhibit lysosomal dysfunction. Credit: Neuroscience News<\/p>\n<p>The scientists identified a new set of genes that contribute to the risk of Parkinson\u2019s disease, which opens the door to previously untapped drug targets for treating PD.<\/p>\n<p>More than 10 million people worldwide are living with PD, the second-most common neurodegenerative disease after Alzheimer\u2019s disease.\u00a0<\/p>\n<p>The study\u00a0was published April 10 in the journal\u00a0Science.\u00a0<\/p>\n<p>\u201cOur study reveals that a combination of genetic factors plays a role in the manifestation of diseases like Parkinson\u2019s disease, which means that therapeutic targeting of several key pathways will have to be considered for such disorders,\u201d said corresponding author\u00a0Dr. Dimitri Krainc, chair of Davee department of neurology and director of the Feinberg Neuroscience Institute at Northwestern University Feinberg School of Medicine.\u00a0\u00a0<\/p>\n<p>\u201cIt also is possible to identify such genetic factors in susceptible individuals by studying tens of thousands of patients, which is challenging and costly,\u201d Krainc said.<\/p>\n<p>\u201cInstead,\u00a0we used a\u00a0genome-wide CRISPR interference screen\u00a0to silence each of the protein-coding human genes in cells and identified those important for PD pathogenesis.\u201d<\/p>\n<p><strong>Variants in Commander genes contribute to PD\u00a0<\/strong><\/p>\n<p>The study discovered that a group of 16 proteins, called Commander, comes together to play a previously unrecognized role in delivering specific proteins to the lysosome, a part of the cell that acts like a recycling center, breaking down waste materials, old cell parts and other unwanted substances.<\/p>\n<p>Previous research has found the greatest risk factor for developing Parkinson\u2019s disease and dementia with Lewy bodies (DLB) is carrying a pathogenic variant in the\u00a0GBA1\u00a0gene. These harmful variants reduce the activity of an enzyme called glucocerebrosidase (GCase), which is important for cells\u2019 recycling process in lysosomes.<\/p>\n<p>However, it has been unknown why some people who carry pathogenic GBA1 variants develop PD whereas others do not.\u00a0To address this, the current study identified Commander complex genes and corresponding proteins that modulate GCase activity specifically in the lysosome.<\/p>\n<p>By examining the genomes from two independent cohorts (the UK Biobank and AMP-PD), the scientists found loss-of-function variants in Commander genes in people with PD compared to those without it.\u00a0<\/p>\n<p>\u201cThis suggests that loss-of-function variants in these genes increase Parkinson\u2019s disease risk,\u201d Krainc said.\u00a0\u00a0<\/p>\n<p><strong>New drug targets to improve lysosomal function\u00a0<\/strong><\/p>\n<p>Lysosomal dysfunction \u2014 or when a cell\u2019s recycling system malfunctions \u2014 is a common feature of several neurodegenerative diseases, including PD.<\/p>\n<p>This study reveals that the Commander complex plays an important role in maintaining lysosomal function, suggesting that drugs that help Commander proteins work better might also improve the cell\u2019s recycling system.\u00a0<\/p>\n<p>Future research will need to determine the extent to which the Commander complex plays a role in other neurodegenerative disorders that exhibit lysosomal dysfunction.\u00a0<\/p>\n<p>\u201cIf Commander dysfunction is observed in these individuals, drugs that target Commander could hold broader therapeutic potential for treating disorders with lysosomal dysfunction,\u201d Krainc said.<\/p>\n<p>\u201cIn this context, Commander-targeting drugs could also complement other PD treatments, such as therapies aiming to increase lysosomal GCase activity, as potential combinatorial therapy.\u201d<\/p>\n<p>Other Northwestern authors include first co-authors postdoctoral fellow Georgia Minakaki and research assistant professor of neurology\u00a0Nathaniel Safren, as well as postdoctoral fellow Bernabe I. Bustos, and assistant professor of neurology\u00a0Dr. Niccolo Mencacci.<\/p>\n<p><strong>Funding: <\/strong>Funding for this study was provided by Research Program Award (R35).\u00a0\u00a0<\/p>\n<p>About this genetics and Parkinson\u2019s disease research news<\/p>\n<p class=\"has-background\" style=\"background-color:#ffffe8\"><strong>Author: <\/strong><a href=\"http:\/\/neurosciencenews.com\/cdn-cgi\/l\/email-protection#c1aab2a0acb4a4adb2aeaf81afaeb3b5a9b6a4b2b5a4b3afefa4a5b4\" target=\"_blank\" rel=\"noreferrer noopener\">Kristin Samuelson<\/a><br \/><strong>Source: <\/strong><a href=\"https:\/\/northwestern.edu\" target=\"_blank\" rel=\"noreferrer noopener\">Northwestern University<\/a><br \/><strong>Contact: <\/strong>Kristin Samuelson \u2013 Northwestern 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:\/\/dx.doi.org\/10.1126\/science.adq6650\" target=\"_blank\" rel=\"noreferrer noopener\">Commander complex regulates lysosomal function and is implicated in Parkinson\u2019s disease risk<\/a>\u201d by Dimitri Krainc et al. Science<\/p>\n<p><strong>Abstract<\/strong><\/p>\n<p><strong>Commander complex regulates lysosomal function and is implicated in Parkinson\u2019s disease risk<\/strong><\/p>\n<p>Variants in\u00a0GBA1\u00a0resulting in decreased lysosomal glucocerebrosidase (GCase) activity are a common risk factor for Parkinson\u2019s disease (PD) and dementia with Lewy bodies (DLB). Incomplete penetrance of\u00a0GBA1\u00a0variants suggests that additional genes contribute to PD and DLB manifestation.<\/p>\n<p>By using a pooled genome-wide CRISPR interference screen, we identified copper metabolism MURR1 domain\u2013containing 3 (COMMD3) protein, a component of the COMMD\/coiled-coil domain\u2013containing protein 22 (CCDC22)\/CCDC93 (CCC) and Commander complexes, as a modifier of GCase and lysosomal activity.<\/p>\n<p>Loss of COMMD3 increased the release of lysosomal proteins through extracellular vesicles, leading to their impaired delivery to endolysosomes and consequent lysosomal dysfunction. Rare variants in the Commander gene family were associated with increased PD risk.<\/p>\n<p>Thus, COMMD genes and related complexes regulate lysosomal homeostasis and may represent modifiers in PD and other neurodegenerative diseases associated with lysosomal dysfunction.<\/p>\n","protected":false},"excerpt":{"rendered":"Summary: Researchers have long wondered why some people with high-risk Parkinson\u2019s gene variants develop the disease while others&hellip;\n","protected":false},"author":2,"featured_media":16801,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[3846],"tags":[215,11363,267,219,233,220,11364,11365,70,16,15],"class_list":{"0":"post-16800","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-genetics","8":"tag-brain-research","9":"tag-commander-gene","10":"tag-genetics","11":"tag-neurobiology","12":"tag-neurology","13":"tag-neuroscience","14":"tag-northwestern-university","15":"tag-parkinsons-disease","16":"tag-science","17":"tag-uk","18":"tag-united-kingdom"},"share_on_mastodon":{"url":"https:\/\/pubeurope.com\/@uk\/114331276011522407","error":""},"_links":{"self":[{"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/posts\/16800","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/comments?post=16800"}],"version-history":[{"count":0,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/posts\/16800\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/media\/16801"}],"wp:attachment":[{"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/media?parent=16800"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/categories?post=16800"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/tags?post=16800"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}