{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T22:09:11Z","timestamp":1787004551429,"version":"build-2736575974"},"reference-count":144,"publisher":"Portland Press Ltd.","issue":"7","license":[{"start":{"date-parts":[[2021,10,8]],"date-time":"2021-10-08T00:00:00Z","timestamp":1633651200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,12,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Age-associated neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD) are an unmet health need, with significant economic and societal implications, and an ever-increasing prevalence. Membrane lipid rafts (MLRs) are specialised plasma membrane microdomains that provide a platform for intracellular trafficking and signal transduction, particularly within neurons. Dysregulation of MLRs leads to disruption of neurotrophic signalling and excessive apoptosis which mirrors the final common pathway for neuronal death in ALS, PD and AD. Sphingomyelinase (SMase) and phospholipase (PL) enzymes process components of MLRs and therefore play central roles in MLR homeostasis and in neurotrophic signalling. We review the literature linking SMase and PL enzymes to ALS, AD and PD with particular attention to attractive therapeutic targets, where functional manipulation has been successful in preclinical studies. We propose that dysfunction of these enzymes is upstream in the pathogenesis of neurodegenerative diseases and to support this we provide new evidence that ALS risk genes are enriched with genes involved in ceramide metabolism (P=0.019, OR = 2.54, Fisher exact test). Ceramide is a product of SMase action upon sphingomyelin within MLRs, and it also has a role as a second messenger in intracellular signalling pathways important for neuronal survival. Genetic risk is necessarily upstream in a late age of onset disease such as ALS. We propose that manipulation of MLR structure and function should be a focus of future translational research seeking to ameliorate neurodegenerative disorders.<\/jats:p>","DOI":"10.1042\/ebc20210026","type":"journal-article","created":{"date-parts":[[2021,10,10]],"date-time":"2021-10-10T18:26:43Z","timestamp":1633890403000},"page":"999-1011","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Membrane lipid raft homeostasis is directly linked to neurodegeneration"],"prefix":"10.1042","volume":"65","author":[{"given":"Tobias","family":"Moll","sequence":"additional","affiliation":[{"name":"Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack\u00a0N.G.","family":"Marshall","sequence":"additional","affiliation":[{"name":"Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikita","family":"Soni","sequence":"additional","affiliation":[{"name":"Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sai","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Genetics, Stanford University School of Medicine, Stanford, CA, U.S.A."},{"name":"Center for Genomics and Personalized Medicine, Stanford University School of Medicine, Stanford, CA, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johnathan","family":"Cooper-Knock","sequence":"additional","affiliation":[{"name":"Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5928-2514","authenticated-orcid":false,"given":"Pamela\u00a0J.","family":"Shaw","sequence":"additional","affiliation":[{"name":"Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2021,12,22]]},"reference":[{"key":"2021122211013466200_B1","doi-asserted-by":"publisher","first-page":"4565","DOI":"10.1113\/JP270590","article-title":"Membrane lipid rafts and neurobiology: age-related changes in membrane lipids and loss of neuronal function","volume":"594","author":"Egawa","year":"2016","journal-title":"J. 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