Modulation of alpha-synuclein aggregation by dopamine analogs

Parkinson's disease is a fatal neurodegenerative movement disorder, which affects an estimated four million people worldwide [1]. However, no known cure exists. The action of dopamine on the aggregation of ?-synuclein (?-syn) is associated with the onset of the pathogenesis of the disease and recent studies have revealed that dopamine and its analogs can inhibit aggregation of ?-syn [2-6]. Here, we have used a combined computational and experimental/microscopical approach to investigate the effect of dopamine mimickers on the aggregation of ?-syn. Using computational methods, small molecules were found in the ligand.info database [7], which are structurally and electrostatically similar to dopamine. Molecular dynamics simulations showed that binding to ?-syn is much weaker than that of dopamine, which inhibits fibrillation [8]. Five of the identified molecules were tested in an in vitro fibrillization assay and analyzed by high-resolution atomic force microscopy (AFM) and transmission electron microscopy (TEM)