Direct membrane association drives mitochondrial fission by the Parkinson disease-associated protein alpha-synuclein |
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Authors: | Nakamura Ken Nemani Venu M Azarbal Farnaz Skibinski Gaia Levy Jon M Egami Kiyoshi Munishkina Larissa Zhang Jue Gardner Brooke Wakabayashi Junko Sesaki Hiromi Cheng Yifan Finkbeiner Steven Nussbaum Robert L Masliah Eliezer Edwards Robert H |
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Affiliation: | Department of Neurology and Physiology, University of California, San Francisco, California 94158, USA. |
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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. |
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Keywords: | Membrane Bilayer Mitochondria Neurodegeneration Parkinson Disease Synuclein Mitochondrial Dynamics |
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