{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T14:07:47Z","timestamp":1777039667059,"version":"3.51.4"},"update-to":[{"DOI":"10.1371\/journal.pgen.1008859","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,2,17]],"date-time":"2021-02-17T00:00:00Z","timestamp":1613520000000}}],"reference-count":49,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2021,2,4]],"date-time":"2021-02-04T00:00:00Z","timestamp":1612396800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01NS094252"],"award-info":[{"award-number":["R01NS094252"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG060963"],"award-info":[{"award-number":["R01AG060963"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","award":["1 IK2 BX003244-01A1"],"award-info":[{"award-number":["1 IK2 BX003244-01A1"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["T32AG000057"],"award-info":[{"award-number":["T32AG000057"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NIH","award":["1S10OD021562-01"],"award-info":[{"award-number":["1S10OD021562-01"]}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>\n                    Abnormal protein aggregation within neurons is a key pathologic feature of Parkinson\u2019s disease (PD). The spread of brain protein aggregates is associated with clinical disease progression, but how this occurs remains unclear. Mutations in\n                    <jats:italic>glucosidase<\/jats:italic>\n                    ,\n                    <jats:italic>beta acid 1<\/jats:italic>\n                    (\n                    <jats:italic>GBA<\/jats:italic>\n                    ), which encodes glucocerebrosidase (GCase), are the most penetrant common genetic risk factor for PD and dementia with Lewy bodies and associate with faster disease progression. To explore how\n                    <jats:italic>GBA<\/jats:italic>\n                    mutations influence pathogenesis, we previously created a\n                    <jats:italic>Drosophila<\/jats:italic>\n                    model of\n                    <jats:italic>GBA<\/jats:italic>\n                    deficiency (\n                    <jats:italic>Gba1b<\/jats:italic>\n                    ) that manifests neurodegeneration and accelerated protein aggregation. Proteomic analysis of\n                    <jats:italic>Gba1b<\/jats:italic>\n                    mutants revealed dysregulation of proteins involved in extracellular vesicle (EV) biology, and we found altered protein composition of EVs from\n                    <jats:italic>Gba1b<\/jats:italic>\n                    mutants. Accordingly, we hypothesized that\n                    <jats:italic>GBA<\/jats:italic>\n                    may influence pathogenic protein aggregate spread via EVs. We found that accumulation of ubiquitinated proteins and Ref(2)P,\n                    <jats:italic>Drosophila<\/jats:italic>\n                    homologue of mammalian p62, were reduced in muscle and brain tissue of\n                    <jats:italic>Gba1b<\/jats:italic>\n                    flies by ectopic expression of wildtype GCase in muscle. Neuronal GCase expression also rescued protein aggregation both cell-autonomously in brain and non-cell-autonomously in muscle. Muscle-specific\n                    <jats:italic>GBA<\/jats:italic>\n                    expression reduced the elevated levels of EV-intrinsic proteins and Ref(2)P found in EVs from\n                    <jats:italic>Gba1b<\/jats:italic>\n                    flies. Perturbing EV biogenesis through neutral sphingomyelinase (nSMase), an enzyme important for EV release and ceramide metabolism, enhanced protein aggregation when knocked down in muscle, but did not modify\n                    <jats:italic>Gba1b<\/jats:italic>\n                    mutant protein aggregation when knocked down in neurons. Lipidomic analysis of nSMase knockdown on ceramide and glucosylceramide levels suggested that\n                    <jats:italic>Gba1b<\/jats:italic>\n                    mutant protein aggregation may depend on relative depletion of specific ceramide species often enriched in EVs. Finally, we identified ectopically expressed GCase within isolated EVs. Together, our findings suggest that GCase deficiency promotes accelerated protein aggregate spread between cells and tissues via dysregulated EVs, and EV-mediated trafficking of GCase may partially account for the reduction in aggregate spread.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1008859","type":"journal-article","created":{"date-parts":[[2021,2,6]],"date-time":"2021-02-06T13:54:46Z","timestamp":1612619686000},"page":"e1008859","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":32,"title":["Glucocerebrosidase reduces the spread of protein aggregation in a Drosophila melanogaster model of neurodegeneration by regulating proteins trafficked by extracellular vesicles"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7029-7132","authenticated-orcid":true,"given":"Kathryn A.","family":"Jewett","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9648-2339","authenticated-orcid":true,"given":"Ruth E.","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5190-3910","authenticated-orcid":true,"given":"Chi Q.","family":"Phan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3262-5043","authenticated-orcid":true,"given":"Bernice","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2825-9623","authenticated-orcid":true,"given":"Gillian","family":"Milstein","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9444-4360","authenticated-orcid":true,"given":"Selina","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6058-9337","authenticated-orcid":true,"given":"Lisa F.","family":"Bettcher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9364-933X","authenticated-orcid":true,"given":"Fausto Carnevale","family":"Neto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Danijel","family":"Djukovic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2467-8118","authenticated-orcid":true,"given":"Daniel","family":"Raftery","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5943-9339","authenticated-orcid":true,"given":"Leo J.","family":"Pallanck","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2502-6293","authenticated-orcid":true,"given":"Marie Y.","family":"Davis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,2,4]]},"reference":[{"issue":"Suppl 1","key":"pgen.1008859.ref001","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1007\/s10654-011-9581-6","article-title":"Epidemiology and etiology of Parkinson\u2019s disease: a review of the evidence","volume":"26","author":"K Wirdefeldt","year":"2011","journal-title":"European journal of epidemiology"},{"issue":"9423","key":"pgen.1008859.ref002","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1016\/S0140-6736(04)16305-8","article-title":"Parkinson\u2019s disease.","volume":"363","author":"A Samii","year":"2004","journal-title":"Lancet"},{"issue":"2","key":"pgen.1008859.ref003","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1176\/jnp.14.2.223","article-title":"An essay on the shaking palsy. 1817","volume":"14","author":"J. 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