title: V63 and N65 of overexpressed α-synuclein are involved in mitochondrial dysfunction.
abstract: 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.
authors.affiliation: Center of Parkinson's Disease Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Disease of the Ministry of, Education, Department of Neurobiology Capital Medical University, Beijing 100069, China.
authors.forename: Huilin
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Center of Parkinson's Disease Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Disease of the Ministry of, Education, Department of Neurobiology Capital Medical University, Beijing 100069, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: Center of Parkinson's Disease Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Disease of the Ministry of, Education, Department of Neurobiology Capital Medical University, Beijing 100069, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Wang
authors.affiliation: Center of Parkinson's Disease Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Disease of the Ministry of, Education, Department of Neurobiology Capital Medical University, Beijing 100069, China.
authors.forename: Chunli
authors.initials: C
authors.lastname: Duan
authors.affiliation: Center of Parkinson's Disease Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Disease of the Ministry of, Education, Department of Neurobiology Capital Medical University, Beijing 100069, China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Center of Parkinson's Disease Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Disease of the Ministry of, Education, Department of Neurobiology Capital Medical University, Beijing 100069, China. Electronic address: huiyang@ccum.edu.cn.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
mesh_terms: D000596:Amino Acids / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002470:Cell Survival; D045304:Cytochromes c / Q000378:metabolism; D042967:Electron Transport Complex I / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000502:physiology*; D010300:Parkinson Disease / Q000378:metabolism; D017382:Reactive Oxygen Species; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D017382:Reactive Oxygen Species; D051844:alpha-Synuclein; D045304:Cytochromes c; D053453:Caspase 9; D042967:Electron Transport Complex I; D002118:Calcium
keywords: Mitochondrial calcium; Mitochondrial dysfunction; Parkinson's Disease; α-Synuclein