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000258096 1001_ $$aKumar, Manoj$$b0
000258096 245__ $$aAcid ceramidase involved in pathogenic cascade leading to accumulation of α-synuclein in iPSC model of GBA1-associated Parkinson's disease.
000258096 260__ $$aOxford$$bOxford Univ. Press$$c2023
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000258096 520__ $$aBi-allelic mutations in GBA1, the gene that encodes β-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's 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-DA neurons). We found that compared with gene-edited isogenic controls, GBA1/PD-DA neurons exhibit mammalian target of rapamycin complex 1 (mTORC1) hyperactivity, a block in autophagy, an increase in the levels of phosphorylated α-synuclein (129) and α-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 α-synuclein levels, suggesting that GluSph was responsible for these alterations. Incubation of gene-edited wild type (WT) controls with exogenous GluSph recapitulated the mTOR/α-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 α-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.
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000258096 650_7 $$2NLM Chemicals$$aalpha-Synuclein
000258096 650_7 $$2NLM Chemicals$$aMTOR Inhibitors
000258096 650_7 $$0EC 3.5.1.23$$2NLM Chemicals$$aAcid Ceramidase
000258096 650_7 $$0EC 3.2.1.45$$2NLM Chemicals$$aGlucosylceramidase
000258096 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aTOR Serine-Threonine Kinases
000258096 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aMechanistic Target of Rapamycin Complex 1
000258096 650_2 $$2MeSH$$aHumans
000258096 650_2 $$2MeSH$$aParkinson Disease: metabolism
000258096 650_2 $$2MeSH$$aalpha-Synuclein: genetics
000258096 650_2 $$2MeSH$$aalpha-Synuclein: metabolism
000258096 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: metabolism
000258096 650_2 $$2MeSH$$aMTOR Inhibitors
000258096 650_2 $$2MeSH$$aAcid Ceramidase: genetics
000258096 650_2 $$2MeSH$$aAcid Ceramidase: metabolism
000258096 650_2 $$2MeSH$$aGlucosylceramidase: genetics
000258096 650_2 $$2MeSH$$aGlucosylceramidase: metabolism
000258096 650_2 $$2MeSH$$aGaucher Disease: metabolism
000258096 650_2 $$2MeSH$$aDopaminergic Neurons: metabolism
000258096 650_2 $$2MeSH$$aTOR Serine-Threonine Kinases: genetics
000258096 650_2 $$2MeSH$$aMechanistic Target of Rapamycin Complex 1: genetics
000258096 650_2 $$2MeSH$$aMutation
000258096 650_2 $$2MeSH$$aLysosomes: metabolism
000258096 7001_ $$aSrikanth, Manasa P$$b1
000258096 7001_ $$0P:(DE-2719)2810385$$aDeleidi, Michela$$b2$$udzne
000258096 7001_ $$aHallett, Penelope J$$b3
000258096 7001_ $$aIsacson, Ole$$b4
000258096 7001_ $$00000-0001-6090-0439$$aFeldman, Ricardo A$$b5
000258096 773__ $$0PERI:(DE-600)1474816-2$$a10.1093/hmg/ddad025$$gVol. 32, no. 11, p. 1888 - 1900$$n11$$p1888 - 1900$$tHuman molecular genetics$$v32$$x0964-6906$$y2023
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