Identification of novel phenolic inhibitors from traditional Chinese medicine against toxic α-synuclein aggregation via regulating phase separation.

Parkinson's disease (PD), a neurodegenerative disorder without cure, is characterized by the pathological aggregation of α-synuclein (α-Syn) in Lewy bodies. Classic deposition pathway and condensation pathway contribute to α-Syn aggregation, and liquid-liquid phase separation is the driving force for condensate formation, which subsequently undergo liquid-solid phase separation to form toxic fibrils. Traditional Chinese Medicine (TCM) has a long history in treating neurodegenerative disease; herein, we identified chemicals from herbs that inhibit α-Syn aggregation. We screened commonly prescribed TCMs for PD from the CNKI database and registered patents, 13 chemicals were identified in the TCMSP databases as candidate inhibitors, among which three phenols, forsythoside B (FTSB), echinacoside (ECH), and 4-hydroxyindole (C4-OH) efficiently inhibit α-Syn aggregation. Moreover, FTSB and ECH increase α-Syn fluidity within condensates, inhibit α-Syn transition into amyloid fibrils and reduce fibril-induced toxicity in SH-SY5Y cells. Importantly, they disaggregated preformed α-Syn amyloid fibrils. Notably, in an α-Syn overexpressing NL5901 C. elegans PD model, either FTSB or ECH treatment significantly extended the lifespan and improved the PD-like movement disorders, both in the preventive and therapeutic treatment approaches, by reducing toxic α-Syn inclusion formation and improving the fluidity of α-Syn. Together, we offer new therapeutic candidates targeting phase separation-associated aggregation for PD.