Targeting of α-Syn Condensate Fluidity by Natural Polyphenols to Retard the Amyloid Transition and Ameliorate α-Syn-Caused Neurotoxicity.

The key pathology of Parkinson's disease (PD) is the presence of Lewy bodies, which contain aggregated α-synuclein (α-Syn). Recent studies revealed that liquid-liquid phase separation (LLPS) is critical for α-Syn aggregation. This study investigates the regulatory effects of three food-related natural polyphenols on α-Syn LLPS and amyloid transition. We discovered that, rather than epigallocatechin gallate (EGCG) and gallic acid (GA), tannic acid (TA) dynamically regulates α-Syn LLPS by increasing α-Syn mobility within the condensates. TA promotes α-Syn condensate fusion but retards the liquid-to-solid phase transition, inhibiting α-Syn aggregation. Further studies showed that TA strongly blocks α-Syn seed-induced aggregation in neuronal cells and exerts neuroprotective effects against α-Syn in Caenorhabditis elegans. Our findings demonstrate that the regulation of LLPS-driven α-Syn amyloid aggregation by small molecules differs from that of nucleation-dependent deposition, providing new insights into targeting α-Syn phase separation in the treatment of PD and other protein aggregation-related diseases.