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.
Highlights
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
Identification of the defective genes in NPC disease led to elucidation of the mechanism by which NPC1 and NPC2 proteins mediate the egress of cholesterol from LEs/Ls
No effective treatment is available for NPC disease patients, the remarkable discovery that treatment of Npc1Ϫ/Ϫ and Npc2Ϫ/Ϫ mice with the cholesterolsequestering agent CYCLO improves the neurodegeneration and prolongs life are very encouraging
Summary
Cholesterol is a key component of cellular membranes and is a precursor of steroid hormones and bile acids. The NPC1 gene encodes an LE/L membrane protein that contains 1,254 amino acids, 13 presumed transmembrane domains, a leucine zipper, a lysosomal targeting motif, and a sterol-sensing motif [12] The latter motif is similar to a sequence that has been identified in several proteins involved in cholesterol metabolism. The impaired trafficking of cholesterol in NPC-deficient cells profoundly affects multiple cellular functions such as regulation of lysosomal calcium homeostasis [35], oxidative stress [36, 37], and vesicle trafficking pathways mediated by Rab proteins [28, 29], as well as fusion of LEs/Ls [38]. Because NPC2 transfers cholesterol directly to membranes [23], a possible explanation for this difference between NPC1 and NPC2 is that NPC2 transfers cholesterol from the LE/L lumen directly to the perimeter membrane of LEs/Ls, as well as to transmembrane proteins such as MLN64 and NPC1
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