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• W4319460738 endingPage "1900" @default.
• W4319460738 startingPage "1888" @default.
• W4319460738 abstract "Bi-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." @default.
• W4319460738 created "2023-02-09" @default.
• W4319460738 creator A5000272595 @default.
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• W4319460738 creator A5056933907 @default.
• W4319460738 creator A5058850275 @default.
• W4319460738 creator A5083913641 @default.
• W4319460738 date "2023-02-08" @default.
• W4319460738 modified "2023-10-01" @default.
• W4319460738 title "Acid ceramidase involved in pathogenic cascade leading to accumulation of α-synuclein in iPSC model of <i>GBA1</i>-associated Parkinson’s disease" @default.
• W4319460738 cites W1520064365 @default.
• W4319460738 cites W1767392319 @default.
• W4319460738 cites W1842363969 @default.
• W4319460738 cites W1975932268 @default.
• W4319460738 cites W1992253341 @default.
• W4319460738 cites W1994758211 @default.
• W4319460738 cites W1995863785 @default.
• W4319460738 cites W2028245787 @default.
• W4319460738 cites W2031365272 @default.
• W4319460738 cites W2039151038 @default.
• W4319460738 cites W2041620451 @default.
• W4319460738 cites W2055445325 @default.
• W4319460738 cites W2076107153 @default.
• W4319460738 cites W2079378641 @default.
• W4319460738 cites W2081102375 @default.
• W4319460738 cites W2096739914 @default.
• W4319460738 cites W2108865709 @default.
• W4319460738 cites W2121349299 @default.
• W4319460738 cites W2130128490 @default.
• W4319460738 cites W2145954079 @default.
• W4319460738 cites W2151378459 @default.
• W4319460738 cites W2151402740 @default.
• W4319460738 cites W2168784140 @default.
• W4319460738 cites W2170281382 @default.
• W4319460738 cites W2329337854 @default.
• W4319460738 cites W2337871602 @default.
• W4319460738 cites W2388217084 @default.
• W4319460738 cites W2464977649 @default.
• W4319460738 cites W2468936663 @default.
• W4319460738 cites W2474991972 @default.
• W4319460738 cites W2495228129 @default.
• W4319460738 cites W2502172977 @default.
• W4319460738 cites W2523238466 @default.
• W4319460738 cites W2554419816 @default.
• W4319460738 cites W2575296050 @default.
• W4319460738 cites W2593816418 @default.
• W4319460738 cites W2606699511 @default.
• W4319460738 cites W2618015181 @default.
• W4319460738 cites W2620943675 @default.
• W4319460738 cites W2622166486 @default.
• W4319460738 cites W2739756331 @default.
• W4319460738 cites W2746979715 @default.
• W4319460738 cites W2752927128 @default.
• W4319460738 cites W2765638828 @default.
• W4319460738 cites W2774477442 @default.
• W4319460738 cites W2779236324 @default.
• W4319460738 cites W2781619571 @default.
• W4319460738 cites W2795198244 @default.
• W4319460738 cites W2796239609 @default.
• W4319460738 cites W2888867513 @default.
• W4319460738 cites W2892528940 @default.
• W4319460738 cites W2896869836 @default.
• W4319460738 cites W2904321687 @default.
• W4319460738 cites W2938730938 @default.
• W4319460738 cites W2947959833 @default.
• W4319460738 cites W2952002410 @default.
• W4319460738 cites W2964053676 @default.
• W4319460738 cites W2972380093 @default.
• W4319460738 cites W2973429381 @default.
• W4319460738 cites W2973720548 @default.
• W4319460738 cites W2980222857 @default.
• W4319460738 cites W2999421965 @default.
• W4319460738 cites W3009510371 @default.
• W4319460738 cites W3019250405 @default.
• W4319460738 cites W3024990779 @default.
• W4319460738 cites W3028372029 @default.
• W4319460738 cites W3043874315 @default.
• W4319460738 cites W3073842499 @default.
• W4319460738 cites W3080525978 @default.
• W4319460738 cites W3108936441 @default.
• W4319460738 cites W3116848493 @default.
• W4319460738 cites W3123784072 @default.
• W4319460738 cites W3128633971 @default.
• W4319460738 cites W3128935747 @default.
• W4319460738 cites W3133765389 @default.
• W4319460738 cites W3137978738 @default.
• W4319460738 cites W3146457438 @default.
• W4319460738 cites W3162818643 @default.
• W4319460738 cites W3175099911 @default.
• W4319460738 cites W3176286643 @default.
• W4319460738 cites W3179013124 @default.
• W4319460738 cites W3198299654 @default.
• W4319460738 cites W3216778464 @default.
• W4319460738 cites W324351088 @default.
• W4319460738 cites W4200372192 @default.
• W4319460738 cites W4205299346 @default.
• W4319460738 cites W4212887372 @default.

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