Direct membrane association drives mitochondrial fission by the Parkinson disease-associated protein α-synuclein

Ken Nakamura, Venu M. Nemani, Farnaz Azarbal, Gaia Skibinski, Jon M. Levy, Kiyoshi Egami, Larissa Munishkina, Jue Zhang, Brooke Gardner, Junko Wakabayashi, Hiromi Sesaki, Yifan Cheng, Steven Finkbeiner, Robert L. Nussbaum, Eliezer Masliah, Robert H. Edwards

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)20710-20726
Number of pages17
JournalJournal of Biological Chemistry
Volume286
Issue number23
DOIs
StatePublished - Jun 10 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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