期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 53, 期 10, 页码 1857-1867出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2012.09.004
关键词
Huntington disease; Oxidative stress; Striatal cells; Reactive oxygen species; Huntingtin
资金
- Fundacao para a Ciencia e a Tecnologia (FCT), Portugal
- 'COMPETE-Programa Operacional Factores de Competitividade' QREN
- European Union
- FCT [SFRH/BD/41285/2007, SFRH/BPD/34711/2007, SFRH/BPD/44246/2008]
- POPH-Programa Operacional Potencial Humano
- QREN
- [PTDC/SAU-FCF/66421/2006]
- [PTDC/SAU-FCF/108056/2008]
- Fundação para a Ciência e a Tecnologia [SFRH/BPD/44246/2008, SFRH/BD/41285/2007, SFRH/BPD/34711/2007, PTDC/SAU-FCF/108056/2008] Funding Source: FCT
Huntington's disease (HD) is a CAG repeat disorder affecting the HD gene, which encodes for huntingtin (Htt) and is characterized by prominent cell death in the striatum. Oxidative stress was previously implicated in HD neurodegeneration, but the role of the major endogenous antioxidant system, the glutathione redox cycle, has been less studied following expression of full-length mutant Htt (FL-mHtt). Thus, in this work we analyzed the glutathione system in striatal cells derived from HD knock-in mice expressing mutant Htt versus wild-type cells. Mutant cells showed increased intracellular reactive oxygen species (ROS) and caspase-3 activity, which were significantly prevented following treatment with glutathione ethyl ester. Interestingly, mutant cells exhibited an increase in intracellular levels of both reduced and oxidized forms of glutathione, and enhanced activities of glutathione peroxidase (GPx) and glutathione reductase (GRed). Furthermore, glutathione-S-transferase (GST) and gamma-glutamyl transpeptidase (gamma-GT) activities were also increased in mutant cells. Nevertheless, glutamate-cysteine ligase (GCL) and glutathione synthetase (GS) activities and levels of GCL catalytic subunit were decreased in cells expressing FL-mHtt, highly suggesting decreased de novo synthesis of glutathione. Enhanced intracellular total glutathione, despite decreased synthesis, could be explained by decreased extracellular glutathione in mutant cells. This occurred concomitantly with decreased mRNA expression levels and activity of the multidrug resistance protein 1 (Mrp1), a transport protein that mediates cellular export of glutathione disulfide and glutathione conjugates. Additionally, inhibition of Mrp1 enhanced intracellular GSH in wild-type cells only. These data suggest that FL-mHtt affects the export of glutathione by decreasing the expression of Mrp1. Data further suggest that boosting of GSH-related antioxidant defense mechanisms induced by FL-mHtt is insufficient to counterbalance increased ROS formation and emergent apoptotic features in HD striatal cells. (C) 2012 Elsevier Inc. All rights reserved.
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