期刊
MOLECULAR AND CELLULAR NEUROSCIENCE
卷 62, 期 -, 页码 51-59出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.mcn.2014.08.002
关键词
Parkinson's disease; Alpha-synuclein; Mitochondrial dysfunction; Oxidative stress; Alpha-synuclein Ser129 phosphmylation; Protein phosphatase 2A
资金
- Fundacao para a Ciencia e a Tecnologia (FCT), Portugal [PTDC/SAU-NEU/101928/2008, PEst-C/SAU/LA0001/2013-2014]
- COMPETE-Programa Operacional Factores de Competitividade, QREN
- European Union (FEDER-Fundo Europeu de Desenvolvimento Regional)
- FCT [SFRH/BD/25515/2005]
- EMBO Installation Grant
- DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain
- Fundação para a Ciência e a Tecnologia [SFRH/BD/25515/2005, PTDC/SAU-NEU/101928/2008] Funding Source: FCT
Alpha-synuclein (alpha-syn) is a soluble protein highly enriched in presynaptic terminals of neurons. Accumulation of alpha-syn as intracellular filamentous aggregates is a pathological feature of sporadic and familial forms of Parkinson's disease (PD). Changes in alpha-syn post-translational modifications, as well as mitochondrial dysfunction and oxidative stress constitute key pathogenic events of this disorder. Here we assessed the correlation between alpha-syn phosphorylation at serine 129 (Ser129), the formation of reactive oxygen species (ROS) and mitochondrial dysfunction in SH-SY5Y cells expressing A53T mutant or wild-type (WT) alpha-syn, exposed to ferrous iron (FeSO4) and rotenone (complex I inhibitor). Under basal conditions, prolonged expression of A53T mutant alpha-syn altered mitochondria morphology, increased superoxide formation and phosphorylation at Ser129, which was linked to decreased activity of protein phosphatase 2A (PP2A). Exposure to FeSO4 or rotenone enhanced intracellular ROS levels, including superoxide anions, in both types of cells, along with alpha-syn Ser129 phosphorylation and mitochondrial depolarization. Most of these changes were largely evident in A53T mutant alpha-syn expressing cells. Overall, the data suggest that stimuli that promote ROS formation and mitochondrial alterations highly correlate with mutant alpha-syn phosphorylation at Ser129, which may precede cell degeneration in PD. (C) 2014 Elsevier Inc. All rights reserved.
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