Small Molecules Detected by Second-Harmonic Generation Modulate the Conformation of Monomeric alpha-Synuclein and Reduce Its Aggregation in Cells

Proteins are structurally dynamic molecules that perform specialized functions through unique conformational changes accessible in physiological environments. An ability to specifically and selectively control protein function via conformational modulation is an important goal for development of novel therapeutics and studies of protein mechanism in biological networks and disease. Here we applied a second-harmonic generation-based technique for studying protein conformation in solution and in real time to the intrinsically disordered, Parkinson disease related protein alpha-synuclein. From a fragment library, we identified small molecule modulators that bind to monomeric alpha-synuclein in vitro and significantly reduce alpha-synuclein aggregation in a neuronal cell culture model. Our results indicate that the conformation of alpha-synuclein is linked to the aggregation of protein in cells. They also provide support for a therapeutic strategy of targeting specific conformations of the protein to suppress or control its aggregation.