Defective cholesterol trafficking in Niemann-Pick C-deficient cells

FEBS Lett. 2010 Jul 2;584(13):2731-9. doi: 10.1016/j.febslet.2010.04.047. Epub 2010 Apr 21.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Biological Transport / genetics
  • Biological Transport / physiology
  • Carrier Proteins / metabolism
  • Cholesterol / metabolism*
  • Glycoproteins / deficiency
  • Glycoproteins / metabolism
  • Humans
  • Membrane Glycoproteins / deficiency*
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Models, Biological

Substances

  • Carrier Proteins
  • Glycoproteins
  • Membrane Glycoproteins
  • NPC1 protein, human
  • NPC2 protein, human
  • Cholesterol