α-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson's disease.
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Authors
Ludtmann, Marthe HR
Angelova, Plamena R
Horrocks, Mathew
Choi, Minee L
Rodrigues, Margarida
Baev, Artyom Y
Berezhnov, Alexey V
Yao, Zhi
Little, Daniel
Banushi, Blerida
Al-Menhali, Afnan Saleh
Yapom, Ratsuda
Dolt, Karamjit Singh
Jaganjac, Morana
Pavlov, Evgeny V
Abramov, Andrey Y
Gandhi, Sonia
Publication Date
2018-06-12Journal Title
Nat Commun
ISSN
2041-1723
Publisher
Springer Science and Business Media LLC
Volume
9
Issue
1
Pages
2293
Language
eng
Type
Article
Physical Medium
Electronic
Metadata
Show full item recordCitation
Ludtmann, M. H., Angelova, P. R., Horrocks, M., Choi, M. L., Rodrigues, M., Baev, A. Y., Berezhnov, A. V., et al. (2018). α-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson's disease.. Nat Commun, 9 (1), 2293. https://doi.org/10.1038/s41467-018-04422-2
Abstract
Protein aggregation causes α-synuclein to switch from its physiological role to a pathological toxic gain of function. Under physiological conditions, monomeric α-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 α-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 α-synuclein aggregates that interact with the ATP synthase and induce PTP opening, leading to neuronal death. This study shows how the transition of α-synuclein from its monomeric to oligomeric structure alters its functional consequences in Parkinson's disease.
Keywords
Neurons, Mitochondria, Animals, Humans, Rats, Rats, Sprague-Dawley, Parkinson Disease, Reactive Oxygen Species, Mitochondrial Proton-Translocating ATPases, Mitochondrial Membrane Transport Proteins, Coculture Techniques, Patch-Clamp Techniques, Proteomics, Oxidation-Reduction, Lipid Peroxidation, Permeability, alpha-Synuclein, Embryonic Stem Cells, Induced Pluripotent Stem Cells, Mitochondrial Permeability Transition Pore
Identifiers
External DOI: https://doi.org/10.1038/s41467-018-04422-2
This record's URL: https://www.repository.cam.ac.uk/handle/1810/283571
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