title: Lysosomal vitamin E accumulation in Niemann-Pick type C disease.
abstract: Niemann-Pick C disease (NPC) is a neuro-visceral lysosomal storage disorder mainly caused by genetic defects in the NPC1 gene. As a result of loss of NPC1 function large quantities of free cholesterol and other lipids accumulate within late endosomes and lysosomes. In NPC livers and brains, the buildup of lipids correlates with oxidative damage; however the molecular mechanisms that trigger it remain unknown. Here we study potential alterations in vitamin E (α-tocopherol, α-TOH), the most potent endogenous antioxidant, in liver tissue and neurons from NPC1 mice. We found increased levels of α-TOH in NPC cells. We observed accumulation and entrapment of α-TOH in NPC neurons, mainly in the late endocytic pathway. Accordingly, α-TOH levels were increased in cerebellum of NPC1 mice. Also, we found decreased mRNA levels of the α-TOH transporter, α-Tocopherol Transfer Protein (α-TTP), in the cerebellum of NPC1 mice. Finally, by subcellular fractionation studies we detected a significant increase in the hepatic α-TOH content in purified lysosomes from NPC1 mice. In conclusion, these results suggest that NPC cells cannot transport vitamin E correctly leading to α-TOH buildup in the endosomal/lysosomal system. This may result in a decreased bioavailability and impaired antioxidant function of vitamin E in NPC, contributing to the disease pathogenesis.
authors: Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors: Luz Fernanda
authors: LF
authors: Yévenes
authors: Andrés
authors: A
authors: Klein
authors: Juan Francisco
authors: JF
authors: Castro
authors: Tamara
authors: T
authors: Marín
authors: Nancy
authors: N
authors: Leal
authors: Federico
authors: F
authors: Leighton
authors: Alejandra R
authors: AR
authors: Alvarez
authors: Silvana
authors: S
authors: Zanlungo
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001682:Biological Availability; D001692:Biological Transport; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000378:metabolism; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009474:Neurons / Q000378:metabolism; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014810:Vitamin E / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D014810:Vitamin E; D002784:Cholesterol