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Mild mutations in GBA1 cause type\u00a01 non-neuronopathic GD, whereas severe mutations cause types\u20092 and 3 neuronopathic GD (nGD). GCase deficiency results in the accumulation of glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph). GlcSph is formed by deacylation of GlcCer by the lysosomal enzyme acid ceramidase. Brains from patients with nGD have high levels of GlcSph, a lipid believed to play an important role in nGD, but the mechanisms involved remain unclear. To identify these mechanisms, we used human induced pluripotent stem cell-derived neurons from nGD patients. We found that elevated levels of GlcSph activate mammalian target of rapamycin (mTOR) complex 1 (mTORC1), interfering with lysosomal biogenesis and autophagy, which were restored by incubation of nGD neurons with mTOR inhibitors. We also found that inhibition of acid ceramidase prevented both, mTOR hyperactivity and lysosomal dysfunction, suggesting that these alterations were caused by GlcSph accumulation in the mutant neurons. To directly determine whether GlcSph can cause mTOR hyperactivation, we incubated wild-type neurons with exogenous GlcSph. Remarkably, GlcSph treatment recapitulated the mTOR hyperactivation and lysosomal abnormalities in mutant neurons, which were prevented by coincubation of GlcSph with mTOR inhibitors. We conclude that elevated GlcSph activates an mTORC1-dependent pathogenic mechanism that is responsible for the lysosomal abnormalities of nGD neurons. We also identify acid ceramidase as essential to the pathogenesis of nGD, providing a new therapeutic target for treating GBA1-associated neurodegeneration.<\/jats:p>","DOI":"10.1002\/sctm.20-0386","type":"journal-article","created":{"date-parts":[[2021,3,3]],"date-time":"2021-03-03T08:56:04Z","timestamp":1614761764000},"page":"1081-1094","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Elevated Glucosylsphingosine in Gaucher Disease induced Pluripotent Stem Cell Neurons Deregulates Lysosomal Compartment through Mammalian Target of Rapamycin Complex\u00a01"],"prefix":"10.1093","volume":"10","author":[{"given":"Manasa P.","family":"Srikanth","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology \u00a0University of Maryland School of Medicine, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jace W.","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences \u00a0University of Maryland School of Pharmacy, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maureen","family":"Kane","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences \u00a0University of Maryland School of Pharmacy, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ola","family":"Awad","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology \u00a0University of Maryland School of Medicine, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tea Soon","family":"Park","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine, and Division of Pediatric Oncology \u00a0Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elias T.","family":"Zambidis","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine, and Division of Pediatric Oncology \u00a0Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA"}],"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 \u00a0University of Maryland School of Medicine, Baltimore, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,3,3]]},"reference":[{"issue":"4","key":"2022022810534121000_sct312911-bib-0001","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1093\/hmg\/ddt468","article-title":"Neuronal accumulation of glucosylceramide in a mouse model 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