Modulation of Alpha-Synuclein Conformational Ensemble and Aggregation Pathways by Dopamine and Related Molecules

Dopaminergic neurons are constantly threatened by the thin boundaries between functional a-synuclein (AS) structural disorder and pathogenic aggregation, and between dopamine (DA) neurotransmitter activity and accumulation of cytotoxic by-products. The possibilities of developing drugs for Parkinson's disease (PD) depend on our understanding of the molecular mechanisms that cause or accompany the pathological structural changes in AS. This review focuses on the three interconnected aspects of AS conformational transitions, its aggregation pathways and ligand binding. Specifically, the interactions of AS with DA, DA metabolites, DA analogs and DA agonists are considered. Recent advances in the field are discussed with reference to the structural properties of AS and the methodologies employed. Although several issues are still object of debate, salient structural features of the protein, the aggregates and the ligands can be identified, in the hope of fueling experimental and computational approaches to the discovery of novel disease-modifying agents.