α-Synuclein misfolding and aggregation: Implications in Parkinson's disease pathogenesis

alpha-Synuclein (alpha-Syn) has been extensively studied for its structural and biophysical properties owing to its pathophysiological role in Parkinson's disease (PD). Lewy bodies and Lewy neurites are the pathological hallmarks of PD and contain alpha-Syn aggregates as their major component. It was therefore hypothesized that alpha-Syn aggregation is actively associated with PD pathogenesis. The central role of alpha-Syn aggregation in PD is further supported by the identification of point mutations in alpha-Syn protein associated with rare familial forms of PD. However, the correlation between aggregation propensities of alpha-Syn mutants and their association with PD phenotype is not straightforward. Recent evidence suggested that oligomers, formed during the initial stages of aggregation, are the potent neurotoxic species causing cell death in PD. However, the heterogeneous and unstable nature of these oligomers limit their detailed characterization. alpha-Syn fibrils, on the contrary, are shown to be the infectious agents and propagate in a prion-like manner. Although alpha-Syn is an intrinsically disordered protein, it exhibits remarkable conformational plasticity by adopting a range of structural conformations under different environmental conditions. In this review, we focus on the structural and functional aspects of alpha-Syn and role of potential factors that may contribute to the underlying mechanism of synucleinopathies. This information will help to identify novel targets and develop specific therapeutic strategies to combat Parkinson's and other protein aggregation related neurodegenerative diseases.