title: Altered cholesterol metabolism in Niemann-Pick type C1 mouse brains affects mitochondrial function.
abstract: Niemann-Pick type C1 (NPC1) disease is a fatal hereditary disorder characterized by a defect in cholesterol trafficking and progressive neurodegeneration. Although the NPC1 gene has been identified, the molecular mechanism responsible for neuronal dysfunction in brains of patients with NPC1 disease remains unknown. This study demonstrates that the amount of cholesterol within mitochondria membranes is significantly elevated in NPC1 mouse brains and neural cells. In addition, the mitochondrial membrane potential, the activity of ATP synthase, and henceforth the level of ATP are markedly decreased in NPC1 mouse brains and neurons. Importantly, reducing the level of cholesterol within mitochondrial membranes using methyl-beta-cyclodextrin can restore the activity of ATP synthase. Finally, NPC1 neurons show an impaired neurite outgrowth, which can be rescued by exogenous ATP. These results suggest that mitochondrial dysfunctions and subsequent ATP deficiency, which are induced by altered cholesterol metabolism in mitochondria, may be responsible for neuronal impairment in NPC1 disease.
authors.affiliation: Department of Alzheimer's Disease Research, National Institute for Longevity Sciences, 36-3 Gengo, Morioka, Obu, Aichi 474-8522, Japan.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Yu
authors.forename: Jian-Sheng
authors.initials: JS
authors.lastname: Gong
authors.forename: Mihee
authors.initials: M
authors.lastname: Ko
authors.forename: William S
authors.initials: WS
authors.lastname: Garver
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Yanagisawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Michikawa
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000502:physiology; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008564:Membrane Potentials; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000502:physiology*; D025261:Mitochondrial Proton-Translocating ATPases / Q000037:antagonists & inhibitors; D000077296:Niemann-Pick C1 Protein; D009542:Niemann-Pick Diseases / Q000209:etiology / Q000503:physiopathology*; D010743:Phospholipids / Q000378:metabolism; D011506:Proteins / Q000235:genetics* / Q000502:physiology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D010743:Phospholipids; D011506:Proteins; D000255:Adenosine Triphosphate; D002784:Cholesterol; D025261:Mitochondrial Proton-Translocating ATPases