{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T14:10:54Z","timestamp":1785161454744,"version":"3.55.0"},"reference-count":87,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T00:00:00Z","timestamp":1675814400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,5,18]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Bi-allelic mutations in GBA1, the gene that encodes \u03b2-glucocerebrosidase (GCase), cause Gaucher disease (GD), whereas mono-allelic mutations do not cause overt pathology. Yet mono- or bi-allelic GBA1 mutations are the highest known risk factor for Parkinson\u2019s disease (PD). GCase deficiency results in the accumulation of glucosylceramide (GluCer) and its deacylated metabolite glucosylsphingosine (GluSph). Brains from patients with neuronopathic GD have high levels of GluSph, and elevation of this lipid in GBA1-associated PD has been reported. To uncover the mechanisms involved in GBA1-associated PD, we used human induced pluripotent stem cell-derived dopaminergic (DA) neurons from patients harboring heterozygote mutations in GBA1 (GBA1\/PD\u2013DA neurons). We found that compared with gene-edited isogenic controls, GBA1\/PD\u2013DA neurons exhibit mammalian target of rapamycin complex 1 (mTORC1) hyperactivity, a block in autophagy, an increase in the levels of phosphorylated \u03b1-synuclein (129) and \u03b1-synuclein aggregation. These alterations were prevented by incubation with mTOR inhibitors. Inhibition of acid ceramidase, the lysosomal enzyme that deacylates GluCer to GluSph, prevented mTOR hyperactivity, restored autophagic flux and lowered \u03b1-synuclein levels, suggesting that GluSph was responsible for these alterations. Incubation of gene-edited wild type (WT) controls with exogenous GluSph recapitulated the mTOR\/\u03b1-synuclein abnormalities of GBA1\/PD neurons, and these phenotypic alterations were prevented when GluSph treatment was in the presence of mTOR inhibitors. We conclude that GluSph causes an aberrant activation of mTORC1, suppressing normal lysosomal functions, including the clearance of pathogenic \u03b1-synuclein species. Our results implicate acid ceramidase in the pathogenesis of GBA1-associated PD, suggesting that this enzyme is a potential therapeutic target for treating synucleinopathies caused by GCase deficiency.<\/jats:p>","DOI":"10.1093\/hmg\/ddad025","type":"journal-article","created":{"date-parts":[[2023,2,7]],"date-time":"2023-02-07T22:11:17Z","timestamp":1675807877000},"page":"1888-1900","source":"Crossref","is-referenced-by-count":19,"title":["Acid ceramidase involved in pathogenic cascade leading to accumulation of \u03b1-synuclein in iPSC model of<i>GBA1<\/i>-associated Parkinson\u2019s disease"],"prefix":"10.1093","volume":"32","author":[{"given":"Manoj","family":"Kumar","sequence":"first","affiliation":[{"name":"University of Maryland School of Medicine Department of Microbiology and Immunology, , Baltimore, MD 21201 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manasa P","family":"Srikanth","sequence":"additional","affiliation":[{"name":"University of Maryland School of Medicine Department of Microbiology and Immunology, , Baltimore, MD 21201 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Deleidi","sequence":"additional","affiliation":[{"name":"German Center for Neurodegenerative Diseases (DZNE) , T\u00fcbingen 72076 , Germany"},{"name":"Harvard Medical School\/McLean Hospital Neuroregeneration Research Institute, , Belmont, MA 02478 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Penelope J","family":"Hallett","sequence":"additional","affiliation":[{"name":"Harvard Medical School\/McLean Hospital Neuroregeneration Research Institute, , Belmont, MA 02478 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ole","family":"Isacson","sequence":"additional","affiliation":[],"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":"University of Maryland School of Medicine Department of Microbiology and Immunology, , Baltimore, MD 21201 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,2,8]]},"reference":[{"key":"2023051907040653100_ref1","doi-asserted-by":"crossref","first-page":"437","DOI":"10.3389\/fneur.2020.00437","article-title":"Exploring sphingolipid implications in neurodegeneration","volume":"11","author":"Alessenko","year":"2020","journal-title":"Front. 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