title: α-Synuclein overexpression impairs mitochondrial function by associating with adenylate translocator.
abstract: α-Synuclein (α-syn), a protein involved in the pathogenesis of Parkinson's disease (PD), is known to accumulate in mitochondria, disrupt mitochondrial function. However, the molecular mechanisms that link these pathological responses have not been investigated. In rats overexpressing α-syn in the substantia nigra (SN) through adeno-associated virus (AAV) transduction, about 50% of tyrosine hydroxylase positive neurons were lost after 24 weeks. Overexpression of α-syn was also associated with morphological deformation of mitochondria and depolarization of the mitochondrial membrane potential (ΔΨm). Both co-immunoprecipitation and confocal microscopy demonstrated that mitochondrial α-syn associated with adenylate translocator (ANT), a component of the mitochondrial permeability transition pore (mPTP). The depolarization of ΔΨm was partially reversed in vitro by bongkrekic acid (BKA), an inhibitor of ANT, suggesting that the molecular association between α-syn and ANT facilitated ΔΨm depolarization. Concomitant with α-syn accumulation in mitochondria, abnormal mitochondrial morphology, ΔΨm depolarization, and loss of TH-positive neurons, there was a decrease in apoptosis-inducing factor (AIF) within the mitochondrial matrix, suggesting possible translocation to the cytosol. Our findings suggest that overexpression of α-syn may cause mitochondrial defects in dopaminergic neurons of the substantia nigra through an association with adenylate translocator and activation of mitochondria-dependent cell death pathways. Disruption of normal mitochondrial function may contribute to the loss of dopaminergic neurons in Parkinson's disease.
authors.affiliation: Beijing Institute for Neuroscience, Department of Neurobiology, Capital Medical University, Beijing Center of Neural Regeneration and Repair, Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Beijing 100069, China.
authors.forename: Yuangang
authors.initials: Y
authors.lastname: Zhu
authors.forename: Chunli
authors.initials: C
authors.lastname: Duan
authors.forename: Li
authors.initials: L
authors.lastname: Lü
authors.forename: Hua
authors.initials: H
authors.lastname: Gao
authors.forename: Chunli
authors.initials: C
authors.lastname: Zhao
authors.forename: Shun
authors.initials: S
authors.lastname: Yu
authors.forename: Kenji
authors.initials: K
authors.lastname: Uéda
authors.forename: Piu
authors.initials: P
authors.lastname: Chan
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
mesh_terms: D000818:Animals; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001865:Bongkrekic Acid / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D000226:Mitochondrial ADP, ATP Translocases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000166:cytology; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051033:Apoptosis Inducing Factor; D051844:alpha-Synuclein; D001865:Bongkrekic Acid; D000226:Mitochondrial ADP, ATP Translocases; D004298:Dopamine