Targeting Gpr52 lowers mutant HTT levels and rescues Huntington's disease-associated phenotypes
文献类型：期刊论文
| 作者 | Song, Haikun2; Li, Hexuan2; Guo, Shimeng3; Pan, Yuyin2; Fu, Yuhua2; Zhou, Zijian2; Li, Zhaoyang2; Wen, Xue2; Sun, Xiaoli2; He, Bingqing3,4 |
| 刊名 | BRAIN
 |
| 出版日期 | 2018-06 |
| 卷号 | 141页码:1782-1798 |
| ISSN号 | 0006-8950 |
| 关键词 | GPCR target validation polyQ neurodegeneration antagonists |
| DOI | 10.1093/brain/awy081 |
| 文献子类 | Article |
| 英文摘要 | Lowering the levels of disease-causing proteins is an attractive treatment strategy for neurodegenerative disorders, among which Huntington's disease is an appealing disease for testing this strategy because of its monogenetic nature. Huntington's disease is mainly caused by cytotoxicity of the mutant HTT protein with an expanded polyglutamine repeat tract. Lowering the soluble mutant HTT may reduce its downstream toxicity and provide potential treatment for Huntington's disease. This is hard to achieve by small-molecule compound drugs because of a lack of effective targets. Here we demonstrate Gpr52, an orphan G protein-coupled receptor, as a potential Huntington's disease drug target. Knocking-out Gpr52 significantly reduces mutant HTT levels in the striatum and rescues Huntington's disease-associated behavioural phenotypes in a knock-in Huntington's disease mouse model expressing endogenous mutant Htt. Importantly, a novel Gpr52 antagonist E7 reduces mutant HTT levels and rescues Huntington's disease-associated phenotypes in cellular and mouse models. Our study provides an entry point for Huntington's disease drug discovery by targeting Gpr52. |
| WOS关键词 | ACID TAGGING BONCAT ; MOUSE MODEL ; PROTEIN ; CELLS ; AUTOPHAGY ; REVERSAL ; MOTOR ; NEURODEGENERATION ; NEUROPATHOLOGY ; IDENTIFICATION |
| 资助项目 | National Key Research and Development Program of China[2016YFC0905100] ; National Natural Science Foundation of China[91649105] ; National Natural Science Foundation of China[81425024] ; Fudan-SIMM Joint Research Fund[FU-SIMM 20174013] |
| WOS研究方向 | Neurosciences & Neurology |
| 语种 | 英语 |
| 出版者 | OXFORD UNIV PRESS |
| WOS记录号 | WOS:000434113500026 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279732]  |
| 专题 | 国家新药筛选中心 |
| 通讯作者 | Xie, Xin; Lu, Boxun |
| 作者单位 | 1.Univ Plymouth, Peninsula Sch Med, Res Way, Plymouth, Devon, England; 2.Fudan Univ, State Key Lab Med Neurobiol, Sch Life Sci, Neurol Dept,Huashan Hosp, Shanghai, Peoples R China; 3.Chinese Acad Sci, CAS Key Lab Receptor Res, Natl Ctr Drug Screening, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China; 5.Univ Plymouth, Peninsula Sch Dent, Inst Translat & Stratified Med, Res Way, Plymouth, Devon, England |
| 推荐引用方式 GB/T 7714 | Song, Haikun,Li, Hexuan,Guo, Shimeng,et al. Targeting Gpr52 lowers mutant HTT levels and rescues Huntington's disease-associated phenotypes[J]. BRAIN,2018,141:1782-1798. |
| APA | Song, Haikun.,Li, Hexuan.,Guo, Shimeng.,Pan, Yuyin.,Fu, Yuhua.,...&Lu, Boxun.(2018).Targeting Gpr52 lowers mutant HTT levels and rescues Huntington's disease-associated phenotypes.BRAIN,141,1782-1798. |
| MLA | Song, Haikun,et al."Targeting Gpr52 lowers mutant HTT levels and rescues Huntington's disease-associated phenotypes".BRAIN 141(2018):1782-1798. |
入库方式： OAI收割
来源：上海药物研究所
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