Abstract / Description of output
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 localize 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 transition of α-synuclein from its monomeric to oligomeric structure alters its functional consequences in Parkinson’s disease.
Original language | English |
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Article number | 2293 |
Number of pages | 16 |
Journal | Nature Communications |
Volume | 9 |
Early online date | 12 Jun 2018 |
DOIs | |
Publication status | Published - 12 Jun 2018 |
Keywords / Materials (for Non-textual outputs)
- cellular neuroscience
- Mechanisms of disease
- neurological disorders
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Mathew Horrocks
- School of Chemistry - Personal Chair of Biophysics
- EaStCHEM
Person: Academic: Research Active