Yu Linwei, Li Xi, Shi Tianyi, Li Ning, Zhang Donge, Liu Xikai, Xiao Yushuo, Liu Xinran, Petersen Robert B, Xue Weikang, Yu Yanxun V, Hu De-Sheng, Xu Li, Chen Hong, Zheng Ling, Huang Kun, Peng Anlin
School of Pharmacy, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, China.
Wuhan Third hospital, Tongren Hospital of Wuhan University, 241 Pengliuyang Road, Wuhan 430060, China.
Int J Biol Macromol. 2025 Mar;297:139875. doi: 10.1016/j.ijbiomac.2025.139875. Epub 2025 Jan 14.
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.
帕金森病（PD）是一种无法治愈的神经退行性疾病，其特征是α-突触核蛋白（α-Syn）在路易小体中发生病理性聚集。经典沉积途径和凝聚途径促成了α-Syn的聚集，而液-液相分离是凝聚物形成的驱动力，随后凝聚物经历液-固相变以形成有毒的纤维。中医在治疗神经退行性疾病方面有着悠久的历史；在此，我们从草药中鉴定出了抑制α-Syn聚集的化学物质。我们从中国知网数据库和已注册专利中筛选了常用于治疗PD的中药，在中药系统药理学数据库（TCMSP）中鉴定出13种化学物质作为候选抑制剂，其中三种酚类化合物，连翘酯苷B（FTSB）、紫锥菊苷（ECH）和4-羟基吲哚（C4-OH）能有效抑制α-Syn聚集。此外，FTSB和ECH增加了凝聚物中α-Syn的流动性，抑制α-Syn转变为淀粉样纤维，并降低了SH-SY5Y细胞中纤维诱导的毒性。重要的是，它们能解聚预先形成的α-Syn淀粉样纤维。值得注意的是，在过表达α-Syn的NL5901秀丽隐杆线虫PD模型中，无论是预防性还是治疗性治疗，FTSB或ECH处理均能显著延长寿命并改善PD样运动障碍，这是通过减少有毒α-Syn包涵体的形成以及改善α-Syn的流动性来实现的。总之，我们提供了针对PD的相分离相关聚集的新治疗候选物。
