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J Biol Chem. 2011 Jun 10;286(23):20710-26. doi: 10.1074/jbc.M110.213538. Epub 2011 Apr 13.

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

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  • 1Department of Neurology and Physiology, University of California, San Francisco, California 94158, USA.

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.

PMID:
21489994
[PubMed - indexed for MEDLINE]
PMCID:
PMC3121472
Free PMC Article
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