Lysosomal vitamin E accumulation in Niemann-Pick type C disease |
| |
Authors: | Luz Fernanda Yé venes,André s KleinJuan Francisco Castro,Tamara Marí nNancy Leal,Federico LeightonAlejandra R. Alvarez,Silvana Zanlungo |
| |
Affiliation: | a Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chileb Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chilec Departamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chiled Fondap-Center for Genome Regulation, Chile |
| |
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. |
| |
Keywords: | NPC, Niemann-Pick type C disease α-TOH, α-tocopherol (vitamin E) α-TTP, α-Tocopherol Transfer Protein U18, U18666A drug SHB, Sucrose-HEPES Buffer RHN, Rat Hippocampal Neurons Ttpa, gene encoding the α-TOH specific intracellular transporter |
本文献已被 ScienceDirect 等数据库收录! |
|