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

Ludtmann, M H R; Angelova, P R; Horrocks, M H; Choi, M L; Rodrigues, M; Baev, A Y; Berezhnov, A V; Yao, Z; Little, D; Banushi, B; Al-Menhali, A S; Ranasinghe, R T; Whiten, D R; Yapom, R; Dolt, K S; Devine, M J; Gissen, P; Kunath, T; Jaganjac, M; Pavlov, E V; Klenerman, D; Abramov, A Y; Gandhi, S

Authors

M H R Ludtmann

P R Angelova

M H Horrocks

M L Choi

M Rodrigues

A Y Baev

A V Berezhnov

Z Yao

D Little

B Banushi

A S Al-Menhali

R T Ranasinghe

D R Whiten

R Yapom

K S Dolt

M J Devine

P Gissen

T Kunath

M Jaganjac

E V Pavlov

D Klenerman

A Y Abramov

S Gandhi



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.

Citation

Ludtmann, M. H. R., Angelova, P. R., Horrocks, M. H., Choi, M. L., Rodrigues, M., Baev, A. Y., …Gandhi, S. (2018). a-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson’s disease. Nature Communications, 9, 2293. https://doi.org/10.1038/s41467-018-04422-2

Journal Article Type Article
Acceptance Date Apr 20, 2018
Publication Date Jun 10, 2018
Deposit Date Jun 15, 2018
Publicly Available Date Nov 21, 2020
Journal Nature Communications
Publisher Nature Research
Peer Reviewed Peer Reviewed
Volume 9
Pages 2293
DOI https://doi.org/10.1038/s41467-018-04422-2
Public URL https://rvc-repository.worktribe.com/output/1386936

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