title: α-Synuclein Shows High Affinity Interaction with Voltage-dependent Anion Channel, Suggesting Mechanisms of Mitochondrial Regulation and Toxicity in Parkinson Disease.
abstract: Participation of the small, intrinsically disordered protein α-synuclein (α-syn) in Parkinson disease (PD) pathogenesis has been well documented. Although recent research demonstrates the involvement of α-syn in mitochondrial dysfunction in neurodegeneration and suggests direct interaction of α-syn with mitochondria, the molecular mechanism(s) of α-syn toxicity and its effect on neuronal mitochondria remain vague. Here we report that at nanomolar concentrations, α-syn reversibly blocks the voltage-dependent anion channel (VDAC), the major channel of the mitochondrial outer membrane that controls most of the metabolite fluxes in and out of the mitochondria. Detailed analysis of the blockage kinetics of VDAC reconstituted into planar lipid membranes suggests that α-syn is able to translocate through the channel and thus target complexes of the mitochondrial respiratory chain in the inner mitochondrial membrane. Supporting our in vitro experiments, a yeast model of PD shows that α-syn toxicity in yeast depends on VDAC. The functional interactions between VDAC and α-syn, revealed by the present study, point toward the long sought after physiological and pathophysiological roles for monomeric α-syn in PD and in other α-synucleinopathies.
authors.affiliation: From the Program in Physical Biology, Eunice Kennedy Shriver NICHD, National Institutes of Health, Bethesda, Maryland 20892, rostovtt@mail.nih.gov.
authors.forename: Tatiana K
authors.initials: TK
authors.lastname: Rostovtseva
authors.affiliation: From the Program in Physical Biology, Eunice Kennedy Shriver NICHD, National Institutes of Health, Bethesda, Maryland 20892, the Physics Department, University of Massachusetts, Amherst, Massachusetts 01003.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Gurnev
authors.affiliation: the Liver Diseases Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Olga
authors.initials: O
authors.lastname: Protchenko
authors.affiliation: From the Program in Physical Biology, Eunice Kennedy Shriver NICHD, National Institutes of Health, Bethesda, Maryland 20892, the Center for Neutron Research, National Institute of Standards and Technology, Gaithersburg, Maryland 20899, and.
authors.forename: David P
authors.initials: DP
authors.lastname: Hoogerheide
authors.affiliation: the Laboratory of Molecular Biophysics, NHLBI, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Thai Leong
authors.initials: TL
authors.lastname: Yap
authors.affiliation: the Liver Diseases Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Caroline C
authors.initials: CC
authors.lastname: Philpott
authors.affiliation: the Laboratory of Molecular Biophysics, NHLBI, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Lee
authors.affiliation: From the Program in Physical Biology, Eunice Kennedy Shriver NICHD, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Sergey M
authors.initials: SM
authors.lastname: Bezrukov
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D006801:Humans; D008051:Lipid Bilayers / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D060066:Protein Interaction Maps; D051381:Rats; D012441:Saccharomyces cerevisiae; D050995:Voltage-Dependent Anion Channel 1 / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D008051:Lipid Bilayers; D051844:alpha-Synuclein; D050995:Voltage-Dependent Anion Channel 1
keywords: alpha-synuclein; intrinsically disordered proteins; ion channel; mitochondrial transport; neurodegeneration; planar lipid bilayer; voltage-dependent anion channel (VDAC); yeast