期刊
NATURE COMMUNICATIONS
卷 9, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-04422-2
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资金
- NIHR Biomedical Research Centre UCLH
- Wellcome Trust Intermediate Clinical Fellowship [100172/Z/12/A]
- Royal Veterinary College
- Allen Distinguished Investigator Program, through The Paul G. Allen Frontiers Group
- Herchel Smith Fund
- Christ's College, University of Cambridge
- Royal Society Professorship
- Federal Targeted Programme for Research and Development in Priority Areas of Development of the Russian Scientific and Technological Complex [14.616.21.0054]
- Anti Doping Lab Qatar
- American Heart Association [16GRNT27260229]
- National Institute of Health [GM115570-01A1]
- Innovative Medicines Initiative Joint Undertaking [115439]
- European Union's Seventh Framework Programme (FP7)
- NIHR HSDR Programme [14/21/45]
- NIHR GOSH BRC
- Wellcome Trust Clinical Postdoctoral Fellowship [106713/Z/14/Z]
- Academy of Medical Sciences starter grant
- Wellcome Trust [100172/Z/12/A] Funding Source: Wellcome Trust
- MRC [UKDRI-2003, MR/J012831/1] Funding Source: UKRI
Protein aggregation causes a-synuclein to switch from its physiological role to a pathological toxic gain of function. Under physiological conditions, monomeric alpha-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 alpha-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 alpha-synuclein aggregates that interact with the ATP synthase and induce PTP opening, leading to neuronal death. This study shows how the transition of alpha-synuclein from its monomeric to oligomeric structure alters its functional consequences in Parkinson's disease.
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