{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T18:28:09Z","timestamp":1793816889592,"version":"4.6.1"},"reference-count":62,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2020,5,11]],"date-time":"2020-05-11T00:00:00Z","timestamp":1589155200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Parkinson\u2019s UK","award":["G-1704"],"award-info":[{"award-number":["G-1704"]}]},{"name":"Parkinson\u2019s UK","award":["K-1507"],"award-info":[{"award-number":["K-1507"]}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council UK","doi-asserted-by":"crossref","award":["MR\/M006646\/1"],"award-info":[{"award-number":["MR\/M006646\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,6,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Mutations in the GBA gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase), are the most important genetic risk factor for Parkinson disease (PD). GCase activity is also decreased in sporadic PD brains and with normal ageing. Loss of GCase activity impairs the autophagy lysosomal pathway resulting in increased \u03b1-synuclein (\u03b1-syn) levels. Furthermore, elevated \u03b1-syn results in decreased GCase activity. Although the role of \u03b1-syn in PD remains unclear, evidence indicates that aggregated \u03b1-syn fibrils are a pathogenic species in PD, passing between neurons and inducing endogenous native \u03b1-syn to aggregate; spreading pathology through the brain. We have investigated if preformed \u03b1-syn fibrils (PFFs) impair GCase activity in mouse cortical neurons and differentiated dopaminergic cells, and whether GCase deficiency in these models increased the transfer of \u03b1-syn pathology to na\u00efve cells. Neurons treated with PFFs induced endogenous \u03b1-syn to become insoluble and phosphorylated at Ser129 to a greater extent than monomeric \u03b1-syn-treatment. PFFs, but not monomeric \u03b1-syn, inhibited lysosomal GCase activity in these cells and induced the unfolded protein response. Neurons in which GCase was inhibited by conduritol \u03b2-epoxide did not increase the amount of insoluble monomeric \u03b1-syn or its phosphorylation status. Instead the release of \u03b1-syn fibrils from GCase deficient cells was significantly increased. Co-culture studies showed that the transfer of \u03b1-syn pathology to na\u00efve cells was greater from GCase deficient cells. This study suggests that GCase deficiency increases the spread of \u03b1-syn pathology and likely contributes to the earlier age of onset and increased cognitive decline associated with GBA-PD.<\/jats:p>","DOI":"10.1093\/hmg\/ddaa085","type":"journal-article","created":{"date-parts":[[2020,5,6]],"date-time":"2020-05-06T11:24:02Z","timestamp":1588764242000},"page":"1716-1728","source":"Crossref","is-referenced-by-count":65,"title":["Glucocerebrosidase deficiency promotes release of \u03b1-synuclein fibrils from cultured neurons"],"prefix":"10.1093","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8093-0723","authenticated-orcid":false,"given":"Matthew E","family":"Gegg","sequence":"first","affiliation":[{"name":"Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, Rowland Hill Street, London NW3 2PF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guglielmo","family":"Verona","sequence":"first","affiliation":[{"name":"Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London NW3 2PF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony H V","family":"Schapira","sequence":"first","affiliation":[{"name":"Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, Rowland Hill Street, London NW3 2PF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,5,11]]},"reference":[{"key":"2020062904235462300_ref1","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1056\/NEJMoa0901281","article-title":"Multicenter analysis of glucocerebrosidase mutations in Parkinson\u2019s disease","volume":"361","author":"Sidransky","year":"2009","journal-title":"N. 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