热休克蛋白70结合蛋白1诱导星形胶质细胞内源性突变亨廷顿蛋白积聚引起神经元死亡  

Heat shock protein 70 binding protein 1 induces the accumulation of endogenous mutant huntingtin in astrocyte and neuronal death

作　　者：静亮 彭希 覃禹森 祝伟[1] JING Liang;PENG Xi;QIN Yusen(Department of Emergency-Critical Medicine,Tongji Hospital,Tongji Medical College of HUST,Wuhan 430030,China)

机构地区：[1]华中科技大学同济医学院附属同济医院急诊-重症医学科,武汉430030 [2]华中科技大学同济医学院附属同济医院神经内科,武汉430030

出　　处：《临床神经病学杂志》2023年第5期372-377,共6页Journal of Clinical Neurology

基　　金：湖北省自然科学基金面上项目(2023AFB713)。

摘　　要：目的 探讨热休克蛋白70结合蛋白1(HspBP1)在亨廷顿病(HD)发病机制中的作用。方法 构建星形胶质细胞特异性表达的GFAP-HspBP1质粒,分别转染C6、GFAP-HD星形胶质细胞和HD140Q基因敲入(HDKI)小鼠的星形胶质细胞中过表达HspBP1,通过免疫染色法检测亨廷顿蛋白(HTT)和神经元相关蛋白。采用CRISPR/Cas9技术敲除HDKI小鼠纹状体神经元内源性HspBp1基因,采用免疫荧光和Western Blotting法检测HTT表达水平。结果 星形胶质细胞中HspBP1过表达不影响星形胶质细胞的活性,但是却显著增加了突变型HTT(mHTT)在星形胶质细胞中的积聚。HDKI小鼠星形胶质细胞中过表达HspBP1还能够诱导纹状体中神经元广泛死亡。与之相对的,基因敲除HspBp1表达可显著减少神经元内mHTT积聚。结论 HspBP1可诱导星形胶质细胞中mHTT的积聚从而引起神经元死亡。Objective To study the role of heat shock protein 70 binding protein 1(HspBP1) in the pathogenesis of Huntington's disease(HD).Methods The GFAP-HspBP1 plasmid specifically expressed in astrocytes was constructed, and transfected C6, GFAP-HD astrocytes and astrocytes of HD140Q knock-in(HDKI) mice respectively in order to overexpress HspBP1. Huntington protein(HTT) and neuronal proteins were detected by immunostaining. The endogenous HspBp1 in striatal neurons of HDKI mice was knocked out by CRISPR/Cas9 method, and the expression of HTT was detected by immunofluorescence and Western Blotting.Results The overexpression of HspBP1 in astrocytes could not affect the activity of astrocytes, but significantly increased the accumulation of mHTT in astrocytes. Overexpression of HspBP1 in astrocytes of HDKI mice could induce neuronal death in striatum. In contrast, knocking-out of HspBp1 could significantly reduce the accumulation of mHTT in neurons. Conclusion HspBP1 could induce the accumulation of mHTT in astrocytes and neuronal death.

关 键 词：亨廷顿病 热休克蛋白70结合蛋白1 星形胶质细胞 神经元死亡 

分 类 号：R742.2[医药卫生—神经病学与精神病学]