Distinct Molecular Mechanisms Underlie Modulation of Seeded α-Synuclein Aggregation and Toxicity by Salvianolic Acid...

Aggregation and seeded propagation of α-synuclein (α-syn) are central to the pathogenesis of Parkinson's disease and related synucleionopathies. Modulation of seeded aggregation and amplification of pathological α-syn species represents a promising strategy for limiting disease progression. Here, we investigated the effects of naturally derived polyphenolic compounds on α-syn fibrillation, seeded aggregation, and associated cytotoxicity. Among the compounds examined, salvianolic acid B and dihydromyricetin exhibited significant inhibitory effects on α-syn aggregation. Biochemical and biophysical analyses using Thioflavin-T fluorescence, Congo Red binding, and transmission electron microscopy demonstrated that both compounds inhibited fibril formation and altered fibril morphology. Notably, dihydromyricetin efficiently disaggregated preformed fibrils and suppressed seeded fibril elongation, whereas salvianolic acid B primarily delayed aggregation kinetics. Both compounds significantly reduced α-syn-induced cytotoxicity in BE(2)-M17 cells. These findings demonstrate that salvianolic acid B and dihydromyricetin differentially modulate key steps in the α-syn aggregation pathway and reduce associated cellular toxicity. Collectively, these results provide mechanistic insight into the modulation of seeded α-syn aggregation and identify salvianolic acid B and dihydromyricetin as effective modulators of pathological α-syn assembly.