Suppression of MAPK11 or HIPK3 reduces mutant Huntingtin levels in Huntington＇s disease models  

作　　者：Meng Yu Yuhua Fu Yijian Liang Haikun Song Yao Yao Peng Wu Yuwei Yao Yuyin Pan Xue Wen Lixiang Ma Saiyin Hexige Yu Ding Shouqing Luo Boxun Lu 

机构地区：[1]State Key Laboratory of Medical Neurobiology, Huashan Hospital, School of Life Sciences, Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai 200438, China [2]Department of Anatomy and Histology & Embryology, Shanghai Medical College, Fudan University, Shanghai 200032, China [3]Peninsula Schools of Medicine and Dentistry, Institute of Translational and Stratified Medicine, University of Plymouth, Research Way, Plymouth, PL68BU, UK

出　　处：《Cell Research》2017年第12期1441-1465,共25页细胞研究（英文版）

基　　金：The authors wished to thank National Natural Science Foundation of China and Na- tional Key Research and Development Program of China （NSFC 91649105, 2016YFC0905100, and NSFC 31422024） for funding supports. FY is supported by China Postdoctoral Science Foundation （2016M601495）, SL is supported by Medical Research Council （MR/M023605/1）.

摘　　要：Most neurodegenerative disorders are associated with accumulation of disease-relevant proteins. Among them, Huntington disease （HD） is of particular interest because of its monogenetic nature. HD is mainly caused by cytotoxicity of the defective protein encoded by the mutant Huntingtin gene （HTT）. Thus, lowering mutant HTT protein （mHTT） levels would be a promising treatment strategy for HD. Here we report two kinases HIPK3 and MAPKll as positive modulators of mHTT levels both in cells and in vivo. Both kinases regulate mHTT via their kinase activities, suggesting that inhibiting these kinases may have therapeutic values. Interestingly, their effects on HTT levels are mHTT-dependent, providing a feedback mechanism in which mHTT enhances its own level thus contributing to mHTT accumulation and disease progression. Importantly, knockout of MAPKll significantly rescues disease-relevant behavioral phenotypes in a knockin HD mouse model. Collectively, our data reveal new therapeutic entry points for HD and target-discovery approaches for similar diseases.

关 键 词：PolyQ high-throughput screening protein homeostasis KINASE positive feedback mechanism neurodegenerative disorders 

分 类 号：Q2[生物学—细胞生物学]