Gossypol, a novel modulator of VCP, induces autophagic degradation of mutant huntingtin by promoting the formation of VCP/p97-LC3-mHTT complex  

作　　者：Xiao-jing Li Yuan-yuan Zhang Yu-hua Fu Hao Zhang He-xuan Li Quan-fu Li Hai-ling Li Ren-ke Tan Chen-xiao Jiang Wei Jiang Zeng-xia Li Cheng Luo Bo-xun Lu Yong-jun Dang 

机构地区：[1]Key Laboratory of Metabolism and Molecular Medicine,the Ministry of Education,Department of Biochemistry and Molecular Biology,School of Basic Medical Sciences,Fudan University,Shanghai 200032,China [2]Drug Discovery and Design Center,The Center for Chemical Biology,State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [3]Neurology Department at Huashan Hospital,State Key Laboratory of Medical Neurobiology,School of Life Sciences,Fudan University,Shanghai 200438,China

出　　处：《Acta Pharmacologica Sinica》2021年第10期1556-1566,共11页中国药理学报（英文版）

基　　金：This work was supported by the National Natural Science Foundation of China(31270830 and 21572038 to YJD;81870990 to BXL,81625022,91853205,81821005 to CL,31970748 to YHF);the Science and Technology Commission of Shanghai Municipality(18431907100 and 19XD1404700 to C.L);the Development Fund for Shanghai Talents,Fund of State Key Laboratory of Bioorganic and Natural Products Chemistry,and Fund of State Key Laboratory of Drug Research and Chinese Academy of Science(SIMM1601KF-08)。

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±0.6μM.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.

关 键 词：Huntington disease mutant huntingtin protein gossypol acetate VCP LC3 autophagic degradation drug reposition 

分 类 号：R96[医药卫生—药理学] R74[医药卫生—药学]