Journal of Biological Chemistry
Volume 287, Issue 47, 16 November 2012, Pages 39349-39360
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Cell Biology
δ-Tocopherol Reduces Lipid Accumulation in Niemann-Pick Type C1 and Wolman Cholesterol Storage Disorders*

https://doi.org/10.1074/jbc.M112.357707Get rights and content
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Niemann-Pick disease type C (NPC) and Wolman disease are two members of a family of storage disorders caused by mutations of genes encoding lysosomal proteins. Deficiency in function of either the NPC1 or NPC2 protein in NPC disease or lysosomal acid lipase in Wolman disease results in defective cellular cholesterol trafficking. Lysosomal accumulation of cholesterol and enlarged lysosomes are shared phenotypic characteristics of both NPC and Wolman cells. Utilizing a phenotypic screen of an approved drug collection, we found that δ-tocopherol effectively reduced lysosomal cholesterol accumulation, decreased lysosomal volume, increased cholesterol efflux, and alleviated pathological phenotypes in both NPC1 and Wolman fibroblasts. Reduction of these abnormalities may be mediated by a δ-tocopherol-induced intracellular Ca2+ response and subsequent enhancement of lysosomal exocytosis. Consistent with a general mechanism for reduction of lysosomal lipid accumulation, we also found that δ-tocopherol reduces pathological phenotypes in patient fibroblasts from other lysosomal storage diseases, including NPC2, Batten (ceroid lipofuscinosis, neuronal 2, CLN2), Fabry, Farber, Niemann-Pick disease type A, Sanfilippo type B (mucopolysaccharidosis type IIIB, MPSIIIB), and Tay-Sachs. Our data suggest that regulated exocytosis may represent a potential therapeutic target for reduction of lysosomal storage in this class of diseases.

Drug Development
Exocytosis
Lipids
Lysosomal Storage Disease
Vitamin E
delta-Tocopherol
Lysosmal Expcytosis
Niemann-Pick Disease Type C
Wolman Disease

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*

This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program of the National Center for Advancing Translational Sciences, by the Intramural Research Program of the National Human Genome Research Institute, by the Intramural Research Program of the Eunice Kennedy Shriver NICHD, and by NCI, National Institutes of Health, Contract HHSN26120080001E. This work was also supported by a grant from the Ara Parseghian Medical Research Foundation.

This article contains supplemental Table S1 and Figs. S1–S7.

1

Both authors contributed equally to this work.