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alpha-Synuclein is a small (14 kDa), abundant, intrinsically disordered presynaptic protein, whose aggregation is believed to be a critical step in Parkinson's disease (PD). The kinetics of alpha-synuclein fibrillation are consistent with a nucleation-dependent mechanism, in which the critical early stage of the structural transformation involves a partially folded intermediate. Although the basis for the toxic effects of aggregated alpha-synuclein are unknown, it has been proposed that transient oligomers are responsible, possibly by forming pores in membranes. In this Account, I discuss our investigations into the molecular basis for alpha-synuclein aggregation/fibrillation, including factors that either accelerate or inhibit fibrillation, effects of molecular crowding, oxidation, point mutations, and lipid membranes, as well as the variety of conformational and oligomeric states that alpha-synuclein can adopt. It is apparent that neuronal cells must have a very fine balance of factors that control the levels and potential aggregation of alpha-synuclein.
Anthony L. Fink (Fri,) studied this question.