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 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.

Crucial role of protein oligomerization in the pathogenesis of Alzheimer's and Parkinson's diseases

“…a-syn oligomers have been demonstrated to interact with the outer mitochondrial membrane Tom20 and impair mitochondrial protein import. We recently demonstrated that a-syn oligomers localise to the inner mitochondrial membrane and come into close proximity to the ATP synthase, and are able to directly induce classical PTP opening in isolated brain mitochondria, and in intact mitochondria in human neurons [56]. We recently demonstrated that a-syn oligomers localise to the inner mitochondrial membrane and come into close proximity to the ATP synthase, and are able to directly induce classical PTP opening in isolated brain mitochondria, and in intact mitochondria in human neurons [56].…”

Circulating Brain‐Enriched MicroRNAs for Detection and Discrimination of Idiopathic and Genetic Parkinson's Disease

“…Although disease‐causing mutations are only found in 2% of patients, they provide important insights into the pathogenesis of PD. Alpha‐synuclein (SNCA) is a neuronal protein, with pleiotropic functions, central to the disease process. Point mutations, gene duplication, and triplication events in the SNCA locus have been identified in families with autosomal dominant early‐onset PD .…”

The usual suspects, dopamine and alpha‐synuclein, conspire to cause neurodegeneration

“…In another report, α‐synuclein oligomers were able to disturb calcium homeostasis and induce mitochondrial dysfunction when incubated with isolated mitochondria in vitro . α‐Synuclein oligomers, including dopamine‐modified species, were also demonstrated to bind to the mitochondrial receptor TOM20 preventing protein import and cause an increase in mitochondrial permeability transition pore opening . Other potential mechanisms of oligomer toxicity include impairment of microtubule‐kinesin transport and inhibition of SNARE complex assembly, the latter of which was specifically demonstrated with dopamine‐induced oligomer species .…”

“…188 α-Synuclein oligomers, including dopamine-modified species, were also demonstrated to bind to the mitochondrial receptor TOM20 preventing protein import 189 and cause an increase in mitochondrial permeability transition pore opening. 190 Other potential mechanisms of oligomer toxicity include impairment of microtubule-kinesin transport 191 and inhibition of SNARE complex assembly, the latter of which was specifically demonstrated with dopamine-induced oligomer species. 167 Thus, α-synuclein oligomers arising from the pathological interaction with dopamine may cause synaptic dysfunction and cell death through a variety of mechanisms and may represent an important new target in the design of diseasemodifying therapies for PD.…”