期刊
BRAIN RESEARCH
卷 1591, 期 -, 页码 14-26出版社
ELSEVIER
DOI: 10.1016/j.brainres.2014.09.046
关键词
Parkinson's disease; alpha-Synuclein; alpha-Synuclein N terminus; Mitochondrial membrane; permeability; Reactive oxygen species
资金
- National Basic Research Program of China [2011CB504102, 2012CB722407]
- National Natural Science Foundation of China [81371398, 81200995, 31100767, 31271136]
- Natural Science Foundation [7131001]
- Project of Construction of Innovative Teams
- Teacher Career Development for Universities and Colleges Under Beijing Municipality [IDHT20140514]
Parkinson's disease (PD) is a common neurodegenerative movement disorder affecting an increasing number of elderly. Various studies have shown that mitochondrial dysfunction and abnormal protein aggregation are two major contributors to the progression of PD. The N terminus of alpha-synuclein (alpha-Syn/N), which adopts an a-helical conformation upon lipid binding, is essential for membrane interaction; yet its role in mitochondria remains poorly defined. A functional characterization of the alpha-Syn N-terminal domain and investigation of its effect on mitochondrial membrane permeability were undertaken in this study. alpha-Syn/N and alpha-Syn/deIN (amino acids 1-65 and 61-140, respectively) constructs were overexpressed in dopaminergic MN9D cells and primary cortical neurons. A decrease in cell viability was observed in cells transfected with alpha-Syn/N but not alpha-Syn/delN. In addition, an alpha-Syn/N-induced increase in the level of intracellular reactive oxygen species, alteration in mitochondrial morphology, and decrease in mitochondrial membrane potential were accompanied by the activation of mitochondrial permeability transition pores (mPTP). These changes were also associated with a decline in mitochondrial cardiolipin content and interaction with the voltage-dependent anion channel and adenine nucleotide translocator in the mitochondrial membrane. The activation of mPTPs and reduction in cell viability were partially reversed by bongkrekic acid, an inhibitor of adenine nucleotide translocator (ANT), suggesting that the interaction between alpha-Syn and ANT promoted mPTP activation and was toxic to cells. BKA treatment reduced interaction of alpha-Syn/N with ANT and VDAC. These results suggest that the N terminus of alpha-Syn is essential for the regulation of mitochondrial membrane permeability and is a likely factor in the neurodegeneration associated with PD. (C) 2014 Elsevier B.V. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据