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 PavlovDavid Klenerman, Andrey Y. Abramov, Sonia Gandhi

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number2293
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

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Synucleins
Parkinson disease
adenosine triphosphate
oligomers
Oligomers
Parkinson Disease
Permeability
permeability
Adenosine Triphosphate
porosity
death
oxidation
Oxidation
proteins
Bearings (structural)
Agglomeration
mitochondria
stem cells
Mitochondrial Swelling
respiration

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Ludtmann, M. H. R., Angelova, P. R., Horrocks, M. H., Choi, M. L., Rodrigues, M., Baev, A. Y., ... Gandhi, S. (2018). α-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson's disease. Nature Communications, 9(1), [2293]. https://doi.org/10.1038/s41467-018-04422-2

α-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson's disease. / Ludtmann, Marthe H.R.; Angelova, Plamena R.; Horrocks, Mathew H.; Choi, Minee L.; Rodrigues, Margarida; Baev, Artyom Y.; Berezhnov, Alexey V.; Yao, Zhi; Little, Daniel; Banushi, Blerida; Al-Menhali, Afnan Saleh; Ranasinghe, Rohan T.; Whiten, Daniel R.; Yapom, Ratsuda; Dolt, Karamjit Singh; Devine, Michael J.; Gissen, Paul; Kunath, Tilo; Jaganjac, Morana; Pavlov, Evgeny; Klenerman, David; Abramov, Andrey Y.; Gandhi, Sonia.

In: Nature Communications, Vol. 9, No. 1, 2293, 01.12.2018.

Research output: Contribution to journalArticle

Ludtmann, MHR, Angelova, PR, Horrocks, MH, Choi, ML, Rodrigues, M, Baev, AY, Berezhnov, AV, Yao, Z, Little, D, Banushi, B, Al-Menhali, AS, Ranasinghe, RT, Whiten, DR, Yapom, R, Dolt, KS, Devine, MJ, Gissen, P, Kunath, T, Jaganjac, M, Pavlov, E, Klenerman, D, Abramov, AY & Gandhi, S 2018, 'α-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson's disease', Nature Communications, vol. 9, no. 1, 2293. https://doi.org/10.1038/s41467-018-04422-2
Ludtmann, Marthe H.R. ; Angelova, Plamena R. ; Horrocks, Mathew H. ; Choi, Minee L. ; Rodrigues, Margarida ; Baev, Artyom Y. ; Berezhnov, Alexey V. ; Yao, Zhi ; Little, Daniel ; Banushi, Blerida ; Al-Menhali, Afnan Saleh ; Ranasinghe, Rohan T. ; Whiten, Daniel R. ; Yapom, Ratsuda ; Dolt, Karamjit Singh ; Devine, Michael J. ; Gissen, Paul ; Kunath, Tilo ; Jaganjac, Morana ; Pavlov, Evgeny ; Klenerman, David ; Abramov, Andrey Y. ; Gandhi, Sonia. / α-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson's disease. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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