title: α-Synuclein amino terminus regulates mitochondrial membrane permeability.
abstract: 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 α-synuclein (α-Syn/N), which adopts an α-helical conformation upon lipid binding, is essential for membrane interaction; yet its role in mitochondria remains poorly defined. A functional characterization of the α-Syn N-terminal domain and investigation of its effect on mitochondrial membrane permeability were undertaken in this study. α-Syn/N and α-Syn/delN (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 α-Syn/N but not α-Syn/delN. In addition, an α-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 α-Syn and ANT promoted mPTP activation and was toxic to cells. BKA treatment reduced interaction of α-Syn/N with ANT and VDAC. These results suggest that the N terminus of α-Syn is essential for the regulation of mitochondrial membrane permeability and is a likely factor in the neurodegeneration associated with PD.
authors.affiliation: Center for Parkinson׳s Disease, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Department of Neurobiology Capital Medical University, Beijing 100069, China.
authors.forename: Jiamei
authors.initials: J
authors.lastname: Shen
authors.affiliation: Center for Parkinson׳s Disease, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Department of Neurobiology Capital Medical University, Beijing 100069, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Du
authors.affiliation: Center for Parkinson׳s Disease, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases 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 for Parkinson׳s Disease, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases 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 for Parkinson׳s Disease, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Department of Neurobiology Capital Medical University, Beijing 100069, China.
authors.forename: Ge
authors.initials: G
authors.lastname: Gao
authors.affiliation: Center for Parkinson׳s Disease, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Department of Neurobiology Capital Medical University, Beijing 100069, China.
authors.forename: Jianliang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Center for Parkinson׳s Disease, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Department of Neurobiology Capital Medical University, Beijing 100069, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Lu
authors.affiliation: Center for Parkinson׳s Disease, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, Department of Neurobiology Capital Medical University, Beijing 100069, China. Electronic address: huiyang@ccmu.edu.cn.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
mesh_terms: D000818:Animals; D002463:Cell Membrane Permeability / Q000502:physiology*; D002478:Cells, Cultured / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein
keywords: Mitochondrial membrane permeability; Parkinson׳s disease; Reactive oxygen species; α-Synuclein; α-Synuclein N terminus