Zeroing in on the pathogenic form of α-synuclein and its mechanism of neurotoxicity in Parkinson's disease

Parkinson's disease (PD) is linked to mutations in the protein alpha-synuclein, which can exist in vitro in several aggregation states, including a natively unfolded monomer, beta-sheet rich oligomer, or protofibril, and a stable amyloid fibril. This work reviews the current literature that is relevant to two linked questions: which of these species is pathogenic, and what is the mechanism of neurotoxicity? The amyloid fibril, fibrillar aggregates, Lewy bodies, and the alpha-synuclein monomer, which is normally expressed at high levels, are all unlikely to be pathogenic, for reasons discussed here. We therefore favor a toxic protofibril scenario, and propose that the pathogenic species is transiently populated during the process of fibrillization. Toxicity may arise from pore-like protofibrils that cause membrane permeabilization. An approach to testing this hypothesis is discussed.