title: The Niemann-Pick C1 protein in recycling endosomes of presynaptic nerve terminals.
abstract: Niemann-Pick type C (NPC) disease is a fatal, neurodegenerative disorder caused in 95% of cases by loss of function of NPC1, a ubiquitous endosomal transmembrane protein. A biochemical hallmark of NPC deficiency is cholesterol accumulation in the endocytic pathway. Although cholesterol trafficking defects are observed in all cell types, neurons are the most vulnerable to NPC1 deficiency, suggesting a specialized function for NPC1 in neurons. We investigated the subcellular localization of NPC1 in neurons to gain insight into the mechanism of action of NPC1 in neuronal metabolism. We show that NPC1 is abundant in axons of sympathetic neurons and is present in recycling endosomes in presynaptic nerve terminals. NPC1 deficiency causes morphological and biochemical changes in the presynaptic nerve terminal. Synaptic vesicles from Npc1(-/-) mice have normal cholesterol content but altered protein composition. We propose that NPC1 plays a previously unrecognized role in the presynaptic nerve terminal and that NPC1 deficiency at this site might contribute to the progressive neurological impairment in NPC disease.
authors.affiliation: Canadian Institutes for Health Research Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Barbara
authors.initials: B
authors.lastname: Karten
authors.forename: Robert B
authors.initials: RB
authors.lastname: Campenot
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Vance
authors.forename: Jean E
authors.initials: JE
authors.lastname: Vance
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D050356:Lipid Metabolism; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D009474:Neurons / Q000378:metabolism; D000077296:Niemann-Pick C1 Protein; D017729:Presynaptic Terminals / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D016708:Synaptophysin / Q000378:metabolism; D014162:Transfection; D033921:Vesicular Transport Proteins / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; C497045:Npc2 protein, mouse; D011506:Proteins; D016708:Synaptophysin; D033921:Vesicular Transport Proteins; D002784:Cholesterol