TY - JOUR
T1 - α-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson's disease
AU - Ludtmann, Marthe H.R.
AU - Angelova, Plamena R.
AU - Horrocks, Mathew H.
AU - Choi, Minee L.
AU - Rodrigues, Margarida
AU - Baev, Artyom Y.
AU - Berezhnov, Alexey V.
AU - Yao, Zhi
AU - Little, Daniel
AU - Banushi, Blerida
AU - Al-Menhali, Afnan Saleh
AU - Ranasinghe, Rohan T.
AU - Whiten, Daniel R.
AU - Yapom, Ratsuda
AU - Dolt, Karamjit Singh
AU - Devine, Michael J.
AU - Gissen, Paul
AU - Kunath, Tilo
AU - Jaganjac, Morana
AU - Pavlov, Evgeny V.
AU - Klenerman, David
AU - Abramov, Andrey Y.
AU - Gandhi, Sonia
N1 - Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-018-04422-2
DO - 10.1038/s41467-018-04422-2
M3 - Article
C2 - 29895861
AN - SCOPUS:85048378130
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2293
ER -