title: δ-Tocopherol reduces lipid accumulation in Niemann-Pick type C1 and Wolman cholesterol storage disorders.
abstract: 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 Ca(2+) 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.
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Miao
authors.initials: M
authors.lastname: Xu
authors.forename: Ke
authors.initials: K
authors.lastname: Liu
authors.forename: Manju
authors.initials: M
authors.lastname: Swaroop
authors.forename: Forbes D
authors.initials: FD
authors.lastname: Porter
authors.forename: Rohini
authors.initials: R
authors.lastname: Sidhu
authors.forename: Sally
authors.initials: S
authors.lastname: Firnkes
authors.forename: Sally
authors.initials: S
authors.lastname: Finkes
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Ory
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Marugan
authors.forename: Jingbo
authors.initials: J
authors.lastname: Xiao
authors.forename: Noel
authors.initials: N
authors.lastname: Southall
authors.forename: William J
authors.initials: WJ
authors.lastname: Pavan
authors.forename: Cristin
authors.initials: C
authors.lastname: Davidson
authors.forename: Steven U
authors.initials: SU
authors.lastname: Walkley
authors.forename: Alan T
authors.initials: AT
authors.lastname: Remaley
authors.forename: Ulrich
authors.initials: U
authors.lastname: Baxa
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.forename: John C
authors.initials: JC
authors.lastname: McKew
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Austin
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D006224:Cricetinae; D005089:Exocytosis / Q000187:drug effects; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*; D008247:Lysosomes / Q000378:metabolism* / Q000473:pathology; D052556:Niemann-Pick Disease, Type C / Q000378:metabolism* / Q000473:pathology; D024505:Tocopherols / Q000494:pharmacology*; D000091346:Tripeptidyl-Peptidase 1; D015223:Wolman Disease / Q000378:metabolism* / Q000473:pathology
chemical_list: D000091346:Tripeptidyl-Peptidase 1; D002784:Cholesterol; C000717267:TPP1 protein, human; C479072:delta-tocopherol; D024505:Tocopherols; D002118:Calcium