{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T21:27:19Z","timestamp":1785446839324,"version":"3.56.0"},"reference-count":97,"publisher":"Oxford University Press (OUP)","issue":"24","license":[{"start":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T00:00:00Z","timestamp":1762992000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000864","name":"Michael J. Fox Foundation","doi-asserted-by":"publisher","award":["16247"],"award-info":[{"award-number":["16247"]}],"id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000864","name":"Michael J. 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Although GD carriers do not exhibit clinical manifestations, GBA1 mutations are the highest risk factor for Parkinson\u2019s disease (PD) in GD patients and carriers of the disease [1\u20135]. GCase breaks down glucosylceramide (GluCer), a sphingolipid that accumulates in GD. GluCer is deacylated by the lysosomal enzyme acid ceramidase (ACDase) to glucosylsphingosine (GluSph) [6\u20138]. GluSph is neurotoxic and accumulates to high levels in neuronopathic GD brains [9, 10]. However, whether this metabolic pathway involving ACDase plays a role in GBA1-associated PD (GBA1\/PD) is not known. In this report we used induced pluripotent stem cells (hiPSCs) from PD patients harboring heterozygote GBA1 mutations to examine the role of ACDase in promoting \u03b1-synuclein accumulation and aggregation, a hallmark of PD. Compared to isogenic controls, hiPSC-derived PD dopamine (DA) neurons had elevated levels of pathogenic \u03b1-synuclein species. There was also reduced nuclear localization of transcription factor EB (TFEB), impaired autophagy, and decreased levels of cathepsin D (CathD), a lysosomal protease involved in \u03b1-synuclein degradation [11]. Treatment of the mutant DA neurons with a number of different ACDase inhibitors, or CRISPR\/Cas9 knockdown (KD) of the ASAH1 gene, reversed all the phenotypic abnormalities of the mutant DA neurons. We conclude that in GBA1\/PD-DA neurons, ACDase contributes to deregulation of key nodes of the autophagy\/lysosomal pathway (ALP) involved in \u03b1-synuclein clearance. Our results suggest that ACDase is a potential therapeutic target for treating GBA1-associated PD.<\/jats:p>","DOI":"10.1093\/hmg\/ddaf166","type":"journal-article","created":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T03:57:21Z","timestamp":1763006241000},"page":"2075-2087","source":"Crossref","is-referenced-by-count":2,"title":["Inhibition or genetic reduction of\n                    <i>ASAH1<\/i>\n                    \/acid ceramidase restore \u03b1-synuclein clearance in mutant\n                    <i>GBA1<\/i>\n                    dopamine neurons from Parkinson\u2019s patients"],"prefix":"10.1093","volume":"34","author":[{"given":"Manoj","family":"Kumar","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of Maryland School of Medicine , 685 West Baltimore Street, HSF-1, Room 380, Baltimore, MD 21201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6090-0439","authenticated-orcid":false,"given":"Ricardo A","family":"Feldman","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Maryland School of Medicine , 685 West Baltimore Street, HSF-1, Room 380, Baltimore, MD 21201"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,11,13]]},"reference":[{"key":"2025120600472211200_ref1","doi-asserted-by":"publisher","first-page":"986","DOI":"10.1016\/S1474-4422(12)70190-4","article-title":"The link between the GBA gene and parkinsonism","volume":"11","author":"Sidransky","year":"2012","journal-title":"Lancet Neurol"},{"key":"2025120600472211200_ref2","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1212\/WNL.0000000000001315","article-title":"Differential effects of severe vs mild GBA mutations on Parkinson 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