Статья

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

Marthe H. R. LudtmannDepartment of Molecular Neuroscience, UCL Institute of Neurology, London, WC1N 3BG, UKPlamena R. AngelovaDepartment of Molecular Neuroscience, UCL Institute of Neurology, London, WC1N 3BG, UKMathew H. HorrocksUK Dementia Research Institute, University of Edinburgh, Edinburgh, UKMinee L. ChoiSobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UKMargarida RodriguesDepartment of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UKArtyom Y. BaevAlexey V. BerezhnovInstitute of Cell Biophysics, Russian Academy of Sciences, Pushchino, 142290, RussiaZhi YaoSobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UKDaniel LittleMRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London, WC1E 6BT, UKBlerida BanushiMRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London, WC1E 6BT, UKAfnan Saleh Al‐MenhaliToxicology and Multipurpose Department, Anti-Doping Lab Qatar, Sport City Road, PO Box 27775, Doha, QatarRohan T. RanasingheDepartment of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UKDaniel R. WhitenDepartment of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UKRatsuda YapomMRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, The University of Edinburgh, Edinburgh, EH16 4UU, UKKaramjit Singh DoltMRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, The University of Edinburgh, Edinburgh, EH16 4UU, UKMichael J. DevineDepartment of Neuroscience, Physiology and Pharmacology, University College London, London, WC1E 6BT, UKPaul GissenMRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London, WC1E 6BT, UKTilo KunathMRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, The University of Edinburgh, Edinburgh, EH16 4UU, UKMorana JaganjacToxicology and Multipurpose Department, Anti-Doping Lab Qatar, Sport City Road, PO Box 27775, Doha, QatarEvgeny V. PavlovDepartment of Basic Sciences, New York University College of Dentistry, NY, 10010, USADavid KlenermanDepartment of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UKAndrey Y. AbramovDepartment of Molecular Neuroscience, UCL Institute of Neurology, London, WC1N 3BG, UK. [email protected]Sonia GandhiSobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK. [email protected]

2018en

ABI

Аннотация

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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Идентификаторы

DOI: 10.1038/s41467-018-04422-2

Цитирования и источники

Цитирований: 3Использованных источников: 0

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