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

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 pathologi

SUBMITTER: Ludtmann MHR 

PROVIDER: S-EPMC5997668 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature