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dc.contributor.authorSrikanth, M.P.
dc.contributor.authorJones, J.W.
dc.contributor.authorKane, M.
dc.contributor.authorAwad, O.
dc.contributor.authorPark, T.S.
dc.contributor.authorZambidis, E.T.
dc.contributor.authorFeldman, R.A.
dc.date.accessioned2021-04-12T17:10:17Z
dc.date.available2021-04-12T17:10:17Z
dc.date.issued2021-03-03
dc.identifier.urihttp://hdl.handle.net/10713/15268
dc.description.abstractGaucher disease (GD) is a lysosomal storage disorder caused by mutations in GBA1, the gene that encodes lysosomal β‐glucocerebrosidase (GCase). Mild mutations in GBA1 cause type 1 non‐neuronopathic GD, whereas severe mutations cause types 2 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. Copyright 2021 The Authors. STEM CELLS TRANSLATIONAL MEDICINE published by Wiley Periodicals LLC on behalf of AlphaMed Pressen_US
dc.description.sponsorshipThis work was supported by grants from the Maryland Stem CellResearch Fund (MSCRF) #2018-MSCRFD-4246 (R.A.F.),#2019-MSCRFD-5037 (O.A.), and from the Children's GaucherResearch Fund (R.A.F.).en_US
dc.description.urihttps://doi.org/10.1002/sctm.20-0386en_US
dc.language.isoen_USen_US
dc.publisherJohn Wiley and Sons Ltden_US
dc.relation.ispartofStem Cells Translational Medicine
dc.subjectdrug targeten_US
dc.subjectexperimental modelsen_US
dc.subjectiPSCsen_US
dc.subjectneural differentiationen_US
dc.subjectneuropathyen_US
dc.subjectsignal transductionen_US
dc.subjectstem/progenitor cellen_US
dc.titleElevated glucosylsphingosine in Gaucher disease induced pluripotent stem cell neurons deregulates lysosomal compartment through mammalian target of rapamycin complex 1en_US
dc.typeArticleen_US
dc.identifier.doi10.1002/sctm.20-0386


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