Curcumin Interacts with alpha-Synuclein Condensates To Inhibit Amyloid Aggregation under Phase Separation

The amyloid aggregation of alpha-synudein (alpha-Syn) is highly associated with Parkinson's disease (PD). Discovering alpha-Syn amyloid inhibitors is one of the strategies for PD therapies. Recent studies suggested that alpha-Syn undergoes phase separation to accelerate amyloid aggregation. Molecules modulating alpha-Syn phase separation or transition have the potential to regulate amyloid aggregation. Here, we discovered that curcumin, a small natural molecule, interacts with alpha-Syn during phase separation. Our study showed that curcumin neither affects the formation of alpha-Syn condensates nor influences the initial morphology of alpha-Syn condensates. However, curcumin decreases the fluidity of alpha-Syn inside the condensates and efficiently inhibits alpha-Syn from turning into an amyloid. It also inhibits the amyloid aggregations of PD disease-related alpha-Syn E46K and H50Q mutants under phase separation. Furthermore, curcumin can destabilize preformed alpha-Syn amyloid aggregates in the condensates. Together, our findings demonstrate that curcumin regulates alpha-Syn amyloid formation during protein phase separation and reveal that alpha-Syn amyloid aggregation under phase separation can be modulated by small molecules.