{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T02:43:11Z","timestamp":1790476991980,"version":"4.1.0"},"reference-count":88,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T00:00:00Z","timestamp":1746576000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Takeda Pharmaceutical Company Limited","award":["NA"],"award-info":[{"award-number":["NA"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Biallelic mutations in the <jats:italic>glucosylceramidase beta 1<\/jats:italic> (<jats:italic>GBA1<\/jats:italic>) gene are the underlying genetic cause of Gaucher\u2019s disease (GD), resulting in a deficient lysosomal hydrolase and subsequent accumulation of glycosphingolipids. More recently, <jats:italic>GBA1<\/jats:italic> mutations have been identified as the most prevalent genetic risk factor for Parkinson\u2019s disease (PD), associated with more pronounced symptoms characterized by earlier onset and accelerated cognitive decline. In these GBA-associated PD patients the \u03b1-synuclein pathology is more prominent, and recent data suggest a link between \u03b1-synucleinopathies and <jats:italic>GBA1<\/jats:italic> mutations. Here, we explored the effect of <jats:italic>GBA1<\/jats:italic> gene supplementation on the GD phenotypes and \u03b1-synuclein pathology by using the adeno-associated virus (AAV) system. We have compared two AAV serotypes, AAV5 and AAV9, and two different ubiquitous promoters, and demonstrate that both promoters work efficiently albeit not the same <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo.<\/jats:italic> <jats:italic>GBA1<\/jats:italic> overexpression reduces the accumulation of glucosylsphingosine (GlcSph) and restores motor dysfunction in a GD mouse model. We further demonstrate that <jats:italic>GBA1<\/jats:italic> overexpression can dissolve phospho-\u03b1-synuclein aggregation induced by the addition of \u03b1-synuclein pre-formed fibril (PFF) in a mouse primary neuron model suggesting the direct effect of \u03b2-Glucocerebrosidase (GCase) on \u03b1-synuclein accumulation. <jats:italic>In vivo<\/jats:italic>, we show that GCase inhibition can induce insoluble high-molecular-weight \u03b1-synuclein aggregation and that delivery of <jats:italic>GBA1<\/jats:italic> achieves robust reduction of the \u03b1-synuclein aggregates in the mouse brain. In summary, GCase expression not only reduces GlcSph, but also restores GD motor dysfunction and removes \u03b1-synuclein aggregates which are the hallmark for PD and \u03b1-synucleinopathies. AAV delivery of <jats:italic>GBA1<\/jats:italic> is a powerful approach to restore glucocerebrosidase function and to resolve misfolded \u03b1-synuclein protein, with applications for GD and PD.<\/jats:p>","DOI":"10.1371\/journal.pone.0321145","type":"journal-article","created":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T17:28:41Z","timestamp":1746638921000},"page":"e0321145","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["AAV delivery of GBA1 suppresses \u03b1-synuclein accumulation in Parkinson\u2019s disease models and restores functions in Gaucher\u2019s disease models"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-2958-9767","authenticated-orcid":true,"given":"Takuro","family":"Okai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sho","family":"Sato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mugdha","family":"Deshpande","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin-ichi","family":"Matsumoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miyu","family":"Nakayama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syunsuke","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bettina","family":"Strack-Logue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Hioki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maiko","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Proetzel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,5,7]]},"reference":[{"issue":"1","key":"pone.0321145.ref001","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s13024-019-0336-2","article-title":"Glucocerebrosidase 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