Myricetin Inhibits -Synuclein Amyloid Aggregation by Delaying the Liquid-to-Solid Phase Transition

The aggregation of alpha-synuclein (alpha-Syn) is a critical pathological hallmark of Parkinson's disease (PD). Prevention of alpha-Syn aggregation has become a key strategy for treating PD. Recent studies have suggested that alpha-Syn undergoes liquid-liquid phase separation (LLPS) to facilitate nucleation and amyloid formation. Here, we examined the modulation of alpha-Syn aggregation by myricetin, a polyhydroxyflavonol compound, under the conditions of LLPS. Unexpectedly, neither the initial morphology nor the phase-separated fraction of alpha-Syn was altered by myricetin. However, the dynamics of alpha-Syn condensates decreased upon myricetin binding. Further studies showed that myricetin dose-dependently inhibits amyloid aggregation in the condensates by delaying the liquid-to-solid phase transition. In addition, myricetin could disassemble the preformed alpha-Syn amyloid aggregates matured from the condensates. Together, our study shows that myricetin inhibits alpha-Syn amyloid aggregation in the condensates by retarding the liquid-to-solid phase transition and reveals that alpha-Syn phase transition can be targeted to inhibit amyloid aggregation.