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.

Abbreviations: ACAT, acyl-CoA:cholesterol acyltransferase, ALLO, allopregnanolone, CD, cyclodextrin, CE, cholesterol esters, CNS, central nervous system, ER, endoplasmic reticulum, GSL, glycosphingolipid, LDL, low density lipoprotein, LE/L, late endosomes/lysosomes, NPC, Niemann-Pick type C

Keywords: Cholesterol, Ganglioside, Neurodegeneration, Niemann-Pick C, Late endosome/lysosome, Cyclodextrin