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Function of the Niemann–Pick type C proteins and their bypass by cyclodextrin

Vance, Jean E; Peake, Kyle B

Current Opinion in Lipidology: June 2011 - Volume 22 - Issue 3 - p 204–209
doi: 10.1097/MOL.0b013e3283453e69
Lipid metabolism: Edited by Jeffrey S. Cohn

Purpose of review This review summarizes the recent findings on the mechanism of action of the Niemann–Pick type C (NPC) proteins and their bypass by cyclodextrin.

Recent findings NPC disease is caused by dysfunction in either the NPC1 or NPC2 protein. These proteins function in the same pathway for the removal of unesterified cholesterol from late endosomes/lysosomes. In NPC-deficient cells, cholesterol derived from the endocytosis of LDLs becomes sequestered in the late endosomes/lysosomes. Recent studies have indicated that these two cholesterol-binding proteins act in tandem in mediating the egress of cholesterol from the late endosomes/lysosomes. Patches of amino acids on NPC1 and NPC2 appear to interact so that the hydrophobic transfer of cholesterol from NPC2 to NPC1 is achieved. Although no effective treatment for NPC disease is currently available, exciting new studies have shown that treatment of NPC-deficient mice with the cholesterol-binding compound, cyclodextrin, reduces the neurodegeneration and markedly extends the life span of Npc1 −/− mice, suggesting a potential therapeutic approach for the treatment of individuals with NPC disease.

Summary Experimental data are consistent with a model for the sequential action of the NPC1 and NPC2 proteins in moving cholesterol out of the late endosomes/lysosomes. Recent data demonstrate that treatment of NPC-deficient mice with cyclodextrin extends their life span, thereby suggesting a potential therapy for NPC patients.

The Group on Molecular and Cell Biology of Lipids, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada

Correspondence to Dr Jean E. Vance, 328 HMRC, University of Alberta, Edmonton, AB T6G 2S2, Canada Tel: +1 780 492 7250; e-mail:

© 2011 Lippincott Williams & Wilkins, Inc.