title: Defective cholesterol trafficking in Niemann-Pick C-deficient cells.
abstract: 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.
authors.affiliation: Group on the Molecular and Cell Biology of Lipids, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Kyle B
authors.initials: KB
authors.lastname: Peake
authors.forename: Jean E
authors.initials: JE
authors.lastname: Vance
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000235:genetics / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D006023:Glycoproteins / Q000172:deficiency / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D000077296:Niemann-Pick C1 Protein; D033921:Vesicular Transport Proteins
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; C104585:NPC2 protein, human; D000077296:Niemann-Pick C1 Protein; D033921:Vesicular Transport Proteins; D002784:Cholesterol