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

Marthe HR Ludtmann, Plamena R Angelova, Mathew H Horrocks, Minee 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 PavlovDavid Klenerman, Andrey Y Abramov, Sonia Gandhi

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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 localize 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 transition of α-synuclein from its monomeric to oligomeric structure alters its functional consequences in Parkinson’s disease.
Original languageEnglish
Article number2293
Number of pages16
JournalNature Communications
Volume9
Early online date12 Jun 2018
DOIs
Publication statusPublished - 12 Jun 2018

Keywords / Materials (for Non-textual outputs)

  • cellular neuroscience
  • Mechanisms of disease
  • neurological disorders

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