title: Direct membrane association drives mitochondrial fission by the Parkinson disease-associated protein alpha-synuclein.
abstract: The protein α-synuclein has a central role in Parkinson disease, but the mechanism by which it contributes to neural degeneration remains unknown. We now show that the expression of α-synuclein in mammalian cells, including neurons in vitro and in vivo, causes the fragmentation of mitochondria. The effect is specific for synuclein, with more fragmentation by α- than β- or γ-isoforms, and it is not accompanied by changes in the morphology of other organelles or in mitochondrial membrane potential. However, mitochondrial fragmentation is eventually followed by a decline in respiration and neuronal death. The fragmentation does not require the mitochondrial fission protein Drp1 and involves a direct interaction of synuclein with mitochondrial membranes. In vitro, synuclein fragments artificial membranes containing the mitochondrial lipid cardiolipin, and this effect is specific for the small oligomeric forms of synuclein. α-Synuclein thus exerts a primary and direct effect on the morphology of an organelle long implicated in the pathogenesis of Parkinson disease.
authors.affiliation: Department of Neurology and Physiology, University of California, San Francisco, California 94158, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Nakamura
authors.forename: Venu M
authors.initials: VM
authors.lastname: Nemani
authors.forename: Farnaz
authors.initials: F
authors.lastname: Azarbal
authors.forename: Gaia
authors.initials: G
authors.lastname: Skibinski
authors.forename: Jon M
authors.initials: JM
authors.lastname: Levy
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Egami
authors.forename: Larissa
authors.initials: L
authors.lastname: Munishkina
authors.forename: Jue
authors.initials: J
authors.lastname: Zhang
authors.forename: Brooke
authors.initials: B
authors.lastname: Gardner
authors.forename: Junko
authors.initials: J
authors.lastname: Wakabayashi
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sesaki
authors.forename: Yifan
authors.initials: Y
authors.lastname: Cheng
authors.forename: Steven
authors.initials: S
authors.lastname: Finkbeiner
authors.forename: Robert L
authors.initials: RL
authors.lastname: Nussbaum
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: Robert H
authors.initials: RH
authors.lastname: Edwards
mesh_terms: D000818:Animals; D019556:COS Cells; D016923:Cell Death / Q000235:genetics; D002522:Chlorocebus aethiops; D006367:HeLa Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D008567:Membranes, Artificial; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010101:Oxygen Consumption / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D008567:Membranes, Artificial; D051844:alpha-Synuclein