Parkinson's disease (PD), a neurodegenerative disorder without cure, is characterized by the pathological aggregation of alpha-synuclein (alpha-Syn) in Lewy bodies. Classic deposition pathway and condensation pathway contribute to alpha-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 alpha-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 alpha-Syn aggregation. Moreover, FTSB and ECH increase alpha-Syn fluidity within condensates, inhibit alpha-Syn transition into amyloid fibrils and reduce fibril-induced toxicity in SH-SY5Y cells. Importantly, they disaggregated preformed alpha-Syn amyloid fibrils. Notably, in an alpha-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 alpha-Syn inclusion formation and improving the fluidity of alpha-Syn. Together, we offer new therapeutic candidates targeting phase separation-associated aggregation for PD.
基金:
National Key Research and Develop-ment Program of China [2023YFC2507900, 2022YFA0806100, 2023YFC2307000]; Natural Science Foundation of China [31971066, 82273838, 32371171]; Natural Science Foundation of Hubei Province [2021CFA004]; Science and Technology Plan Project of Hubei Province [2022DFE025]; Medical Sub-center of Analytical and Testing Center of Huazhong University of Science and Technology
第一作者机构:[1]Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Pharm, Wuhan 430030, Peoples R China[2]Huazhong Univ Sci & Technol, State Key Lab Diag & Treatment Severe Zoonot Infec, Wuhan 430030, Peoples R China
共同第一作者:
通讯作者:
通讯机构:[1]Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Pharm, Wuhan 430030, Peoples R China[2]Huazhong Univ Sci & Technol, State Key Lab Diag & Treatment Severe Zoonot Infec, Wuhan 430030, Peoples R China[3]Wuhan Univ, Wuhan Hosp 3, Tongren Hosp, 241 Pengliuyang Rd, Wuhan 430060, Peoples R China[9]Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Rong Cheng Biomed Ctr, Wuhan 430030, Peoples R China[*1]Huazhong Univ Sci & Technol, Tongji Sch Pharm, Wuhan 430030, Peoples R China[*2]Wuhan Univ, Wuhan Hosp 3, Wuhan 430060, Peoples R China
推荐引用方式(GB/T 7714):
Yu Linwei,Li Xi,Shi Tianyi,et al.Identification of novel phenolic inhibitors from traditional Chinese medicine against toxic α-synuclein aggregation via regulating phase separation[J].INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES.2025,297:doi:10.1016/j.ijbiomac.2025.139875.
APA:
Yu, Linwei,Li, Xi,Shi, Tianyi,Li, Ning,Zhang, Donge...&Peng, Anlin.(2025).Identification of novel phenolic inhibitors from traditional Chinese medicine against toxic α-synuclein aggregation via regulating phase separation.INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES,297,
MLA:
Yu, Linwei,et al."Identification of novel phenolic inhibitors from traditional Chinese medicine against toxic α-synuclein aggregation via regulating phase separation".INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES 297.(2025)