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

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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 [4]Wuhan Univ, Coll Life Sci, Frontier Sci Ctr Immunol & Metab, Hubei Key Lab Cell Homeostasis, Wuhan 430072, Peoples R China [5]Cent Michigan Univ, Coll Med, Fdn Sci, Mt Pleasant, MI 48859 USA [6]Wuhan Univ, Zhongnan Hosp, Med Res Inst, Dept Neurol, Wuhan 430070, Peoples R China [7]Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Integrated Tradit Chinese & Western Med, Wuhan 430000, Peoples R China [8]Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, China Russia Med Res Ctr Stress Immunol, Wuhan 430000, Peoples R China [9]Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Rong Cheng Biomed Ctr, Wuhan 430030, Peoples R China
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关键词: alpha-Synuclein Inhibitor Phase separation

摘要:
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.

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出版当年[2025]版:
大类 | 2 区 生物学
小类 | 2 区 生化与分子生物学 2 区 应用化学 2 区 高分子科学
最新[2025]版:
大类 | 2 区 生物学
小类 | 2 区 生化与分子生物学 2 区 应用化学 2 区 高分子科学
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出版当年[2023]版:
Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Q1 CHEMISTRY, APPLIED Q1 POLYMER SCIENCE
最新[2023]版:
Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Q1 CHEMISTRY, APPLIED Q1 POLYMER SCIENCE

影响因子: 最新[2023版] 最新五年平均 出版当年[2023版] 出版当年五年平均 出版前一年[2022版]

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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
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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
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