Gossypol, a novel modulator of VCP, induces autophagic degradation of mutant huntingtin by promoting the formation of VCP/p97-LC3-mHTT complex
文献类型：期刊论文
| 作者 | Li, Xiao-jing1; Zhang, Yuan-yuan2; Fu, Yu-hua3; Zhang, Hao2; Li, He-xuan3; Li, Quan-fu1; Li, Hai-ling1; Tan, Ren-ke1; Jiang, Chen-xiao1; Jiang, Wei1 |
| 刊名 | ACTA PHARMACOLOGICA SINICA
 |
| 出版日期 | 2021-01-25 |
| 卷号 | 42期号:10页码:1556-1566 |
| 关键词 | Huntington disease mutant huntingtin protein gossypol acetate VCP LC3 autophagic degradation drug reposition |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/s41401-020-00605-0 |
| 文献子类 | Article |
| 英文摘要 | Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by toxic aggregates of mutant huntingtin protein (mHTT) in the brain. Decreasing mHTT is a potential strategy for therapeutic purpose of HD. Valosin-containing protein (VCP/p97) is a crucial regulator of proteostasis, which regulates the degradation of damaged protein through proteasome and autophagy pathway. Since VCP has been implicated in pathogenesis of HD as well as other neurodegenerative diseases, small molecules that specifically regulate the activity of VCP may be of therapeutic benefits for HD patients. In this study we established a high-throughput screening biochemical assay for VCP ATPase activity measurement and identified gossypol, a clinical approved drug in China, as a novel modulator of VCP. Gossypol acetate dose-dependently inhibited the enzymatic activity of VCP in vitro with IC50 of 6.53 +/- 0.6 mu M. We further demonstrated that gossypol directly bound to the interface between the N and D1 domains of VCP. Gossypol acetate treatment not only lowered mHTT levels and rescued HD-relevant phenotypes in HD patient iPS-derived Q47 striatal neurons and HD knock-in mouse striatal cells, but also improved motor function deficits in both Drosophila and mouse HD models. Taken together, gossypol acetate acted through a gain-of-function way to induce the formation of VCP-LC3-mHTT ternary complex, triggering autophagic degradation of mHTT. This study reveals a new strategy for treatment of HD and raises the possibility that an existing drug can be repurposed as a new treatment of neurodegenerative diseases. |
| WOS关键词 | DISEASE ; VCP/P97 ; PROTEIN ; ATPASE ; CALCINEURIN ; INHIBITORS ; TARGET ; COMMON |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000611452000004 |
| 出版者 | NATURE PUBL GROUP |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309399]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Luo, Cheng; Lu, Bo-xun; Dang, Yong-jun |
| 作者单位 | 1.Fudan Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, Key Lab Metab & Mol Med,Minist Educ, Shanghai 200032, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Ctr Chem Biol,State Key Lab Drug Res, Shanghai 201203, Peoples R China; 3.Fudan Univ, Sch Life Sci, State Key Lab Med Neurobiol, Neurol Dept,Huashan Hosp, Shanghai 200438, Peoples R China |
| 推荐引用方式 GB/T 7714 | Li, Xiao-jing,Zhang, Yuan-yuan,Fu, Yu-hua,et al. Gossypol, a novel modulator of VCP, induces autophagic degradation of mutant huntingtin by promoting the formation of VCP/p97-LC3-mHTT complex[J]. ACTA PHARMACOLOGICA SINICA,2021,42(10):1556-1566. |
| APA | Li, Xiao-jing.,Zhang, Yuan-yuan.,Fu, Yu-hua.,Zhang, Hao.,Li, He-xuan.,...&Dang, Yong-jun.(2021).Gossypol, a novel modulator of VCP, induces autophagic degradation of mutant huntingtin by promoting the formation of VCP/p97-LC3-mHTT complex.ACTA PHARMACOLOGICA SINICA,42(10),1556-1566. |
| MLA | Li, Xiao-jing,et al."Gossypol, a novel modulator of VCP, induces autophagic degradation of mutant huntingtin by promoting the formation of VCP/p97-LC3-mHTT complex".ACTA PHARMACOLOGICA SINICA 42.10(2021):1556-1566. |
入库方式： OAI收割
来源：上海药物研究所
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