Journal
FEBS LETTERS
Volume 584, Issue 13, Pages 2731-2739Publisher
WILEY
DOI: 10.1016/j.febslet.2010.04.047
Keywords
Cholesterol; Ganglioside; Neurodegeneration; Niemann-Pick C; Late endosomes/lysosome; Cyclodextrin
Funding
- National Science and Engineering Research Council of Canada
- Alberta Heritage Foundation for Medical Research
- Canadian Institutes for Health Research
- Ara Parseghian Medical Research Foundation
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Pathways of intracellular cholesterol trafficking are poorly understood at the molecular level. Mutations in Niemann-Pick C (NPC) proteins, NPC1 and NPC2, however, have led to insights into the mechanism by which endocytosed cholesterol is exported from late endosomes/lysosomes (LE/L). Mutations in NPC1, a multi-spanning membrane protein of LE/L, or mutations in NPC2, a soluble luminal protein of LE/L, cause the neurodegenerative disorder NPC disease. This review focuses on data supporting a model in which movement of cholesterol out of LE/L is mediated by the sequential action of the two NPC proteins. We also discuss potential therapies for NPC disease, including evidence that treatment of NPC-deficient mice with the cholesterol-binding compound, cyclodextrin, markedly attenuates neurodegeneration, and increases life-span, of NPC1-deficient mice. (C) 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
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