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

Marthe H. R. Ludtmann, Plamena R. Angelova, Mathew H. Horrocks, Minee L. Choi, Margarida Rodrigues, Artyom Y. Baev, Alexey V. Berezhnov, Zhi Yao, Daniel Little, Blerida Banushi, Afnan Saleh Al-Menhali, Rohan T. Ranasinghe, Daniel R. Whiten, Ratsuda Yapom, Karamjit Singh Dolt, Michael J. Devine, Paul Gissen, Tilo Kunath, Morana Jaganjac, Evgeny V. Pavlov, David Klenerman, Andrey Y. Abramov () and Sonia Gandhi ()
Additional contact information
Marthe H. R. Ludtmann: UCL Institute of Neurology
Plamena R. Angelova: UCL Institute of Neurology
Mathew H. Horrocks: University of Cambridge
Minee L. Choi: UCL Institute of Neurology
Margarida Rodrigues: University of Cambridge
Artyom Y. Baev: Laboratory of Biophysics and Biochemistry
Alexey V. Berezhnov: Institute of Cell Biophysics, Russian Academy of Sciences
Zhi Yao: UCL Institute of Neurology
Daniel Little: University College London
Blerida Banushi: University College London
Afnan Saleh Al-Menhali: Anti-Doping Lab Qatar, Sport City Road, PO Box 27775
Rohan T. Ranasinghe: University of Cambridge
Daniel R. Whiten: University of Cambridge
Ratsuda Yapom: The University of Edinburgh
Karamjit Singh Dolt: The University of Edinburgh
Michael J. Devine: University College London
Paul Gissen: University College London
Tilo Kunath: The University of Edinburgh
Morana Jaganjac: Anti-Doping Lab Qatar, Sport City Road, PO Box 27775
Evgeny V. Pavlov: New York University College of Dentistry
David Klenerman: University of Cambridge
Andrey Y. Abramov: UCL Institute of Neurology
Sonia Gandhi: UCL Institute of Neurology

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04422-2

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