{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T02:08:16Z","timestamp":1784081296554,"version":"3.55.0"},"reference-count":30,"publisher":"S. Karger AG","issue":"1-4","license":[{"start":{"date-parts":[[2012,1,1]],"date-time":"2012-01-01T00:00:00Z","timestamp":1325376000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.karger.com\/Services\/SiteLicenses"},{"start":{"date-parts":[[2012,1,1]],"date-time":"2012-01-01T00:00:00Z","timestamp":1325376000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.karger.com\/Services\/SiteLicenses"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Neurodegener Dis"],"published-print":{"date-parts":[[2012]]},"abstract":"Heterozygous mutations in the glucocerebrosidase gene <i>(GBA1)<\/i> are associated with increased risk for \u03b1-synuclein aggregation disorders (\u2018synucleinopathies\u2019), which include Parkinson\u2019s disease (PD) and dementia with Lewy bodies (DLB). Homozygous <i>GBA1<\/i> mutations lead to reduced GBA1 lysosomal activity underlying three variants of Gaucher disease (GD). Despite the wealth of clinical and genetic evidence supporting the association between mutant genotypes and synucleinopathy risk, the precise mechanisms by which <i>GBA1<\/i> mutations lead to PD and DLB remain unclear. Here, we summarize recent findings that highlight the complexity of this pathogenetic link. In neural cells, both gain and loss of function mechanisms, as conferred by mutant GBA1 expression and activity loss, respectively, seem to promote aberrant \u03b1-synuclein processing. In addition, we draw attention to recent insights gleaned from GD animal models regarding axonal pathology, brain inflammation and memory dysfunction. From a translational perspective, we discuss the concepts of neural enzyme replacement therapy and pharmacological agents as potential treatment strategies for GBA1-associated synucleinopathies. Finally, we touch on the issue whether aberrant \u03b1-synuclein species may coregulate GBA1 activity in the vertebrate brain, thereby providing a reverse link, i.e., between an important synucleinopathy risk factor and the enzyme\u2019s lysosomal function. In summary, several leads connecting <i>GBA1<\/i> mutations with \u03b1-synuclein misprocessing have emerged as potential targets for the treatment of <i>GBA1-<\/i>related synucleinopathies, and possibly, for non-<i>GBA1-<\/i>associated neurodegenerative diseases.<\/jats:p>","DOI":"10.1159\/000335038","type":"journal-article","created":{"date-parts":[[2012,2,9]],"date-time":"2012-02-09T12:27:56Z","timestamp":1328790476000},"page":"195-202","source":"Crossref","is-referenced-by-count":24,"title":["Mutant <i>GBA1<\/i> Expression and Synucleinopathy Risk: First Insights from Cellular and Mouse Models"],"prefix":"10.1159","volume":"10","author":[{"given":"S. Pablo","family":"Sardi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priyanka","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seng H.","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lamya S.","family":"Shihabuddin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael G.","family":"Schlossmacher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"127","published-online":{"date-parts":[[2012,2,9]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","DOI":"10.1016%2Fj.ymgme.2004.08.015"},{"key":"ref2","doi-asserted-by":"publisher","DOI":"10.1016%2FS0140-6736%2808%2961522-6"},{"key":"ref3","doi-asserted-by":"publisher","DOI":"10.1007%2Fs11910-010-0102-x"},{"key":"ref4","doi-asserted-by":"publisher","DOI":"10.1038%2F42166"},{"key":"ref5","doi-asserted-by":"publisher","DOI":"10.1002%2Fana.22400"},{"key":"ref6","doi-asserted-by":"publisher","DOI":"10.1093%2Fhmg%2Fddq292"},{"key":"ref7","doi-asserted-by":"publisher","DOI":"10.1016%2Fj.neuro.2009.06.009"},{"key":"ref8","doi-asserted-by":"publisher","DOI":"10.1016%2Fj.cell.2011.06.001"},{"key":"ref9","doi-asserted-by":"publisher","DOI":"10.1038%2Fnchembio850"},{"key":"ref10","doi-asserted-by":"publisher","DOI":"10.1016%2Fj.ymgme.2010.12.014"},{"key":"ref11","doi-asserted-by":"publisher","DOI":"10.1073%2Fpnas.1108197108"},{"key":"ref12","doi-asserted-by":"publisher","DOI":"10.1212%2F01.wnl.0000276989.17578.02"},{"key":"ref13","doi-asserted-by":"publisher","DOI":"10.1212%2F01.wnl.0000327823.81237.d1"},{"key":"ref14","doi-asserted-by":"publisher","DOI":"10.1212%2F01.wnl.0000304039.11891.29"},{"key":"ref15","doi-asserted-by":"publisher","DOI":"10.1016%2Fj.molmed.2011.05.003"},{"key":"ref16","doi-asserted-by":"publisher","DOI":"10.1093%2Fqjmed%2F94.8.399"},{"key":"ref17","doi-asserted-by":"publisher","DOI":"10.1016%2Fj.ymgme.2004.04.011"},{"key":"ref18","doi-asserted-by":"publisher","DOI":"10.1016%2FS1474-4422%2809%2970062-6"},{"key":"ref19","doi-asserted-by":"publisher","DOI":"10.1073%2Fpnas.0708086104"},{"key":"ref20","doi-asserted-by":"publisher","DOI":"10.1016%2FS1096-7192%2803%2900071-4"},{"key":"ref21","doi-asserted-by":"publisher","DOI":"10.1212%2F01.wnl.0000230215.41296.18"},{"key":"ref22","doi-asserted-by":"publisher","DOI":"10.1093%2Fbrain%2Fawp044"},{"key":"ref23","doi-asserted-by":"publisher","DOI":"10.1074%2Fjbc.M111.237859"},{"key":"ref24","doi-asserted-by":"publisher","DOI":"10.1007%2Fs00401-010-0741-7"},{"key":"ref25","doi-asserted-by":"publisher","DOI":"10.1016%2FS0896-6273%2803%2900024-2"},{"key":"ref26","doi-asserted-by":"publisher","DOI":"10.1056%2FNEJM200502173520719"},{"key":"ref27","doi-asserted-by":"publisher","DOI":"10.1002%2Fmds.21399"},{"key":"ref28","doi-asserted-by":"publisher","DOI":"10.1016%2Fj.nbd.2009.03.002"},{"key":"ref29","doi-asserted-by":"publisher","DOI":"10.1001%2Farchneurol.2011.11"},{"key":"ref30","doi-asserted-by":"publisher","DOI":"10.1194%2Fjlr.M500202-JLR200"}],"container-title":["Neurodegenerative Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.karger.com\/Article\/Pdf\/335038","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.karger.com\/Article\/Pdf\/335038","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T18:53:00Z","timestamp":1745434380000},"score":1,"resource":{"primary":{"URL":"https:\/\/karger.com\/article\/doi\/10.1159\/000335038"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012]]},"references-count":30,"journal-issue":{"issue":"1-4","published-online":{"date-parts":[[2012,4,1]]},"published-print":{"date-parts":[[2012,4,19]]}},"URL":"https:\/\/doi.org\/10.1159\/000335038","archive":["Portico"],"relation":{},"ISSN":["1660-2854","1660-2862"],"issn-type":[{"value":"1660-2854","type":"print"},{"value":"1660-2862","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012]]}}}