alpha-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson's disease

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Protein aggregation causes a-synuclein to switch from its physiological role to a pathological toxic gain of function. Under physiological conditions, monomeric alpha-synuclein improves ATP synthase efficiency. Here, we report that aggregation of monomers generates beta sheet-rich oligomers that localise to the mitochondria in close proximity to several mitochondrial proteins including ATP synthase. Oligomeric alpha-synuclein impairs complex I-dependent respiration. Oligomers induce selective oxidation of the ATP synthase beta subunit and mitochondrial lipid peroxidation. These oxidation events increase the probability of permeability transition pore (PTP) opening, triggering mitochondrial swelling, and ultimately cell death. Notably, inhibition of oligomer-induced oxidation prevents the pathological induction of PTP. Inducible pluripotent stem cells (iPSC)-derived neurons bearing SNCA triplication, generate alpha-synuclein aggregates that interact with the ATP synthase and induce PTP opening, leading to neuronal death. This study shows how the transition of alpha-synuclein from its monomeric to oligomeric structure alters its functional consequences in Parkinson's disease.
Publisher
NATURE PUBLISHING GROUP
Issue Date
2018-06
Language
English
Article Type
Article
Citation

NATURE COMMUNICATIONS, v.9

ISSN
2041-1723
DOI
10.1038/s41467-018-04422-2
URI
http://hdl.handle.net/10203/305028
Appears in Collection
BC-Journal Papers(저널논문)
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