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• W4283523764 abstract "Abstract Lysosomes function as a primary site for catabolism and cellular signaling. These organelles digest a variety of substrates received through endocytosis, secretion and autophagy with the help of resident acid hydrolases. Lysosomal enzymes are folded in the endoplasmic reticulum (ER) and trafficked to lysosomes via Golgi and endocytic route. The inability of hydrolase trafficking due to mutations or mutations in its receptor or cofactor leads to cargo accumulation (storage) in lysosomes, resulting in lysosome storage disorder (LSD). In Gaucher’s disease (GD), the lysosomes accumulate glucosylceramide due to a lack of β-glucocerebrosidase (β-GC) activity that causes lysosome enlargement/dysfunction. We hypothesize that improving the trafficking of mutant β-GC to lysosomes may delay the progression of GD. RNAi screen using high throughput based lysosomal enzyme activity assay followed by reporter trafficking assay utilizing β-GC-mCherry lead to the identification of nine potential phosphatases. Depletion of these phosphatases in HeLa cells enhanced the β-GC activity by increasing the folding and trafficking of Gaucher’s mutants to the lysosomes. Consistently, the lysosomes in primary fibroblasts from GD patients restored their function upon the knockdown of these phosphatases. Thus, these studies provide evidence that altering phosphatome activity possibly delays the GD and forms an alternative therapeutic strategy for this genetic disease. Key points Phosphatome RNAi screen identified both activators and inhibitors of cellular glucocerebrosidase activity Depletion of selective phosphatases in HeLa cells improved the folding and trafficking of mutant β-glucocerebrosidase to lysosomes Knockdown of selective phosphatases restored the low basal β-glucocerebrosidase activity to that of wild-type in primary cells derived from Gaucher’s disease patients Depletion of selective phosphatases displayed variable β-GC activity in neuropathic and non-neuropathic Gaucher’s disease patient cells" @default.
• W4283523764 created "2022-06-27" @default.
• W4283523764 creator A5032539390 @default.
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• W4283523764 date "2022-06-25" @default.
• W4283523764 modified "2023-10-13" @default.
• W4283523764 title "Restoration of β-GC trafficking improves the lysosome function in Gaucher’s disease" @default.
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• W4283523764 doi "https://doi.org/10.1101/2022.06.23.497394" @default.
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