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Cited by 513Parkinson's Disease Mechanisms and TreatmentsMitochondrial Function and PathologyAlzheimer's disease research and treatments

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

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Ludtmann, Marthe H. R., Angelova, Plamena R., Horrocks, Mathew H., Choi, Minee L., Rodrigues, Margarida, Baev, Artyom Y., Berezhnov, Alexey V., Yao, Zhi +15 more·2018·Nature Communications
DOI 10.1038/s41467-018-04422-2PMC PMC5997668
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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.

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  • Other in vitro studies revealed oligomeric α-synuclein induced mitochondrial dysfunction and neuronal death through multiple mechanisms.

    “But other in vitro studies revealed that oligomeric α-synuclein induced mitochondrial dysfunction and neuronal death through multiple mechanisms.56,57”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [56]

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Authors
Ludtmann, M. H. R., Angelova, P. R., Horrocks, M. H., Choi, M. L., Rodrigues, M., Baev, A. Y., Berezhnov, A. V., Yao, Z., Little, D., Banushi, B., Al-Menhali, A. S., Ranasinghe, R. T., Whiten, D. R., Yapom, R., Dolt, K. S., Devine, M. J., Gissen, P., Kunath, T., Jaganjac, M., Pavlov, E. V., Klenerman, D., Abramov, A. Y., & Gandhi, S.
Affiliations
  • Royal Veterinary College (GB)
  • UCL Queen Square Institute of Neurology (GB)
  • University of Cambridge (GB)
  • The Francis Crick Institute (GB)
  • Russian Academy of Sciences (RU)
  • MRC Laboratory for Molecular Cell Biology (GB)
  • MRC Centre for Regenerative Medicine (GB)
  • Anti-Doping Laboratory (QA)
  • New York University (US)
Corresponding author
  • Abramov, Andrey Y.
  • Gandhi, Sonia
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2018-06-12
Volume
9
Issue
1
Pages
2293-2293
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-018-04422-2
PMC
PMC5997668
OpenAlex
W2805954533
Cited by
513
References
4
Citations by year
2026: 45 · 2025: 63 · 2024: 68 · 2023: 49 · 2022: 69 · 2021: 71 · 2020: 81 · 2019: 57 · 2018: 10
FWCI
37.18
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Apollo (cc-by)
Funders
  • American Heart Association (16GRNT27260229)
  • Wellcome Trust (100172/Z/12/Z, 100172/Z/12A, 106713/Z/14/Z)
  • European Federation of Pharmaceutical Industries and Associations
  • Paul G. Allen Frontiers Group
  • National Institute for Health and Care Research (14/21/45)
  • Parkinson's UK (F-0902)
  • Academy of Medical Sciences (AMS-SGCL5-Gandhi)
  • European Commission (2014‐2020, 2007–2013, 115439)
  • University College London Hospitals NHS Foundation Trust
  • Innovative Medicines Initiative (115439)
  • Royal Veterinary College
  • Medical Research Council (MR/J012831/1)
  • Christ's College, University of Cambridge
  • NIHR Great Ormond Street Hospital Biomedical Research Centre
  • National Institute of General Medical Sciences (R01GM115570)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
alpha-synuclein oligomers, ATP synthase, mitochondrial permeability transition pore, Parkinson's disease, protein aggregation, lipid peroxidation, mitochondrial swelling, neuronal cell death, SNCA triplication, iPSC-derived neurons, mitochondrial dysfunction
MeSH terms
Mitochondrial Permeability Transition Pore, Animals, Humans, Mitochondria, Neurons, Oxidation-Reduction, Parkinson Disease, Permeability, Lipid Peroxidation, Rats, Sprague-Dawley, Reactive Oxygen Species, Patch-Clamp Techniques, Coculture Techniques, Mitochondrial Proton-Translocating ATPases, Mitochondrial Membrane Transport Proteins, Proteomics, Rats, alpha-Synuclein, Embryonic Stem Cells, Induced Pluripotent Stem Cells

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