Zeroing in on the Pathogenic Form of α-Synuclein and Its Mechanism of Neurotoxicity in Parkinson's Disease

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Abstract
Parkinson's disease (PD) is linked to mutations in the protein α-synuclein, which can exist in vitro in several aggregation states, including a natively unfolded monomer, a β-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 α-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.