α-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson’s disease
journal contributionposted on 2020-08-27, 15:35 authored by Marthe HR 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, Sonia Gandhi
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.
AnimalsCoculture TechniquesEmbryonic Stem CellsHumansInduced Pluripotent Stem CellsLipid PeroxidationMitochondriaMitochondrial Membrane Transport ProteinsMitochondrial Proton-Translocating ATPasesNeuronsOxidation-ReductionParkinson DiseasePatch-Clamp TechniquesPermeabilityProteomicsRatsRats, Sprague-DawleyReactive Oxygen Speciesalpha-SynucleinGandhi - sec