title: Function of the Niemann-Pick type C proteins and their bypass by cyclodextrin.
abstract: OBJECTIVE
  This review summarizes the recent findings on the mechanism of action of the Niemann-Pick type C (NPC) proteins and their bypass by cyclodextrin.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: The Group on Molecular and Cell Biology of Lipids, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. jean.vance@ualberta.ca
authors.forename: Jean E
authors.initials: JE
authors.lastname: Vance
authors.forename: Kyle B
authors.initials: KB
authors.lastname: Peake
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D057847:Lipid Regulating Agents / Q000494:pharmacology*; D008247:Lysosomes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D000077296:Niemann-Pick C1 Protein; D009542:Niemann-Pick Diseases / Q000188:drug therapy / Q000235:genetics; D033921:Vesicular Transport Proteins; D047392:beta-Cyclodextrins / Q000494:pharmacology*
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D057847:Lipid Regulating Agents; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; C104585:NPC2 protein, human; D000077296:Niemann-Pick C1 Protein; D033921:Vesicular Transport Proteins; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D002784:Cholesterol