V63 and N65 of overexpressed α-synuclein are involved in mitochondrial dysfunction
| Autor: | Hui Yang, Huilin Zhang, Chunli Duan, Xiaomin Wang, Jia Liu, Xue Wang |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Voltage-dependent anion channel Cell Survival animal diseases Apoptosis Mitochondrion Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Animals Humans Amino Acids Molecular Biology Membrane Potential Mitochondrial Alpha-synuclein Electron Transport Complex I biology General Neuroscience MPTP Adenine nucleotide translocator Cytochromes c Parkinson Disease Molecular biology Caspase 9 Mitochondria nervous system diseases HEK293 Cells 030104 developmental biology nervous system chemistry Mitochondrial permeability transition pore alpha-Synuclein biology.protein DNAJA3 Calcium Neurology (clinical) ATP–ADP translocase Reactive Oxygen Species 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | Brain Research. 1642:308-318 |
| ISSN: | 0006-8993 |
| DOI: | 10.1016/j.brainres.2016.04.002 |
| Popis: | Parkinson's Disease (PD) is one of the most common neurodegenerative diseases. α-Synuclein (α-Syn)-encoded by SNCA, the first-identified PD-related gene-is the main component of Lewy bodies, which are a pathological hallmark of PD. We previously reported that α-Syn accumulates in mitochondria in PD, causing mitochondrial abnormalities and disrupting mitochondrial membrane potential (Δψm) and mitochondrial potential transition pore (mPTP) opening by interacting with the voltage-dependent anion channel (VDAC) and adenine nucleotide translocator. However, the mechanistic basis of mitochondrial impairment caused by α-Syn has yet to be elucidated. It has been suggested that the amino acid residues Q62, V63, and N65 of α-Syn are important for the interaction of the protein with membranes. To investigate whether this underlies the mitochondrial dysfunction induced by α-Syn overexpression, we mutated these residues to alanine and transfected HEK293T and MN9D cells with the mutated forms of α-Syn protein. The V63A and N65A mutations prevented mitochondrial Ca(2+) overload and Δψm dysregulation as well as complex I inactivation and reactive oxygen species production while blocking mPTP opening and caspase 9 activation, possibly by reducing α-Syn accumulation in mitochondria. These results indicate that V63 and N65 are critical residues mediating mitochondrial inactivation. These findings provide novel insight into the molecular events contributing to PD pathogenesis. |
| Databáze: | OpenAIRE |
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