title: Niemann-Pick C disease and mobilization of lysosomal cholesterol by cyclodextrin.
abstract: Niemann-Pick type C (NPC) disease is a lysosomal storage disease in which endocytosed cholesterol becomes sequestered in late endosomes/lysosomes (LEs/Ls) because of mutations in either the NPC1 or NPC2 gene. Mutations in either of these genes can lead to impaired functions of the NPC1 or NPC2 proteins and progressive neurodegeneration as well as liver and lung disease. NPC1 is a polytopic protein of the LE/L limiting membrane, whereas NPC2 is a soluble protein in the LE/L lumen. These two proteins act in tandem and promote the export of cholesterol from LEs/Ls. Consequently, a defect in either NPC1 or NPC2 causes cholesterol accumulation in LEs/Ls. In this review, we summarize the molecular mechanisms leading to NPC disease, particularly in the CNS. Recent exciting data on the mechanism by which the cholesterol-sequestering agent cyclodextrin can bypass the functions of NPC1 and NPC2 in the LEs/Ls, and mobilize cholesterol from LEs/Ls, will be highlighted. Moreover, the possible use of cyclodextrin as a valuable therapeutic agent for treatment of NPC patients will be considered.
authors.affiliation: The Group on Molecular and Cell Biology of Lipids and Department of Medicine, University of Alberta, Edmonton, AB, Canada.
authors.forename: Jean E
authors.initials: JE
authors.lastname: Vance
authors.affiliation: Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS, Canada.
authors.forename: Barbara
authors.initials: B
authors.lastname: Karten
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism; D003505:Cyclodextrins / Q000627:therapeutic use*; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D033921:Vesicular Transport Proteins
chemical_list: D002352:Carrier Proteins; D003505:Cyclodextrins; 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
keywords: Purkinje cells; astrocytes; cholesterol homeostasis; endoplasmic reticulum; gangliosides; lysosomal storage disease; microglia; neurodegenerative disease; neurons