More than 10 million people worldwide are living with PD<\/a>, the second-most common neurodegenerative disease after Alzheimer\u2019s disease. One of the research challenges in PD is the question of why some people with variants that increase the risk of PD go on to develop the disease, while others, with the same variants do not. It\u2019s been assumed that additional genetic factors may play a role. This team hopes their work will point to as-yet untapped drug targets for PD and related conditions.<\/p>\nThe Northwestern team used CRISPR interference to systematically examine every gene in the human genome.<\/p>\n
\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 Dimitri Krainc, MD, PhD, chair of the Davee Department of Neurology and director of the Feinberg Neuroscience Institute at Northwestern University Feinberg School of Medicine.\u00a0<\/p>\n
\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. \u201cInstead, we used a genome-wide CRISPR interference screen to silence each of the protein-coding human genes in cells and identified those important for PD pathogenesis.\u201d<\/p>\n
Previous research has found the greatest risk factor for developing PD and dementia with Lewy bodies is carrying a pathogenic variant in the GBA1 gene. These harmful variants reduce the activity of an enzyme called glucocerebrosidase (GCase), which is important for cells\u2019 recycling process in lysosomes. However, some people who carry pathogenic GBA1 variants develop PD whereas others do not.<\/p>\n
The Northwestern study identified Commander complex genes and corresponding proteins that modulate GCase activity specifically in the lysosome. 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.<\/p>\n
\u201cThis suggests that loss-of-function variants in these genes increase Parkinson\u2019s disease risk,\u201d Krainc said.\u00a0\u00a0<\/p>\n
Lysosomal dysfunction\u2014or when a cell\u2019s recycling system malfunctions\u2014is a common feature of several neurodegenerative diseases, including PD. 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.<\/p>\n
Future research, they said, will need to determine the extent to which the Commander complex plays a role in other neurodegenerative disorders that exhibit lysosomal dysfunction.<\/p>\n
\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. \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","protected":false},"excerpt":{"rendered":"Credit: nopparit \/ Getty Images \/ E+ New genes that affect the risk of Parkinson\u2019s disease (PD) have…\n","protected":false},"author":2,"featured_media":22125,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[3846],"tags":[231,14192,267,6910,11922,11365,11923,70,11920,16,15],"class_list":{"0":"post-22124","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-genetics","8":"tag-alzheimers-disease","9":"tag-crispr","10":"tag-genetics","11":"tag-human-genome","12":"tag-news-features","13":"tag-parkinsons-disease","14":"tag-precision-medicine","15":"tag-science","16":"tag-topics","17":"tag-uk","18":"tag-united-kingdom"},"share_on_mastodon":{"url":"https:\/\/pubeurope.com\/@uk\/114342298050966587","error":""},"_links":{"self":[{"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/posts\/22124","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=22124"}],"version-history":[{"count":0,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/posts\/22124\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/media\/22125"}],"wp:attachment":[{"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/media?parent=22124"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/categories?post=22124"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/tags?post=22124"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}
![\"Neuron](\"https:\/\/www.europesays.com\/uk\/wp-content\/uploads\/2025\/04\/GettyImages-2146153516-696x391.jpg\" "\\"2146153516\\"\/")
Credit: nopparit \/ Getty Images \/ E+<\/p>\n