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

Author

Listed:
  • Marthe H. R. Ludtmann

    (UCL Institute of Neurology
    Royal Veterinary College)

  • Plamena R. Angelova

    (UCL Institute of Neurology)

  • Mathew H. Horrocks

    (University of Cambridge
    University of Edinburgh
    University of Edinburgh)

  • Minee L. Choi

    (UCL Institute of Neurology
    The Francis Crick Institute)

  • Margarida Rodrigues

    (University of Cambridge)

  • Artyom Y. Baev

    (Laboratory of Biophysics and Biochemistry)

  • Alexey V. Berezhnov

    (Institute of Cell Biophysics, Russian Academy of Sciences)

  • Zhi Yao

    (UCL Institute of Neurology
    The Francis Crick Institute)

  • Daniel Little

    (University College London)

  • Blerida Banushi

    (University College London)

  • Afnan Saleh Al-Menhali

    (Anti-Doping Lab Qatar, Sport City Road, PO Box 27775)

  • Rohan T. Ranasinghe

    (University of Cambridge)

  • Daniel R. Whiten

    (University of Cambridge)

  • Ratsuda Yapom

    (The University of Edinburgh)

  • Karamjit Singh Dolt

    (The University of Edinburgh)

  • Michael J. Devine

    (University College London
    University College London)

  • Paul Gissen

    (University College London)

  • Tilo Kunath

    (The University of Edinburgh)

  • Morana Jaganjac

    (Anti-Doping Lab Qatar, Sport City Road, PO Box 27775)

  • Evgeny V. Pavlov

    (New York University College of Dentistry)

  • David Klenerman

    (University of Cambridge
    University of Cambridge)

  • Andrey Y. Abramov

    (UCL Institute of Neurology)

  • Sonia Gandhi

    (UCL Institute of Neurology
    The Francis Crick Institute)

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.

Suggested Citation

  • 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 , 2018. "α-synuclein oligomers interact with ATP synthase and open the permeability transition pore in Parkinson’s disease," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04422-2
    DOI: 10.1038/s41467-018-04422-2
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