Supression of MAPK11 or HIPK3 reduces mutant HTT levels in HD models

发布日期2017-10-19 10:34 来源:本站

Meng Yu1, *, Yuhua Fu1, *, Yijiang Liang1, *, Haikun Song1, Yao Yao1, Peng Wu1, Yuwei Yao1, Yuyin Pan1, Xue Wen1, Lixiang Ma2, Saiyin Hexige1, Yu Ding1, Shouqing Luo3, Boxun Lu1, 4

1State Key Laboratory of Medical Neurobiology, Huashan Hospital, School of Life Sciences, Fudan University, Shanghai, China. 

2Department of Anatomy and Histology & Embryology, Shanghai Medical College, Fudan University, Shanghai, China. 

3Penin-sula Schools of Medicine and Dentistry, Institute of Translational and Stratified Medicine, University of Plymouth, Research Way,Plymouth, UK. 

4Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai, China.

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 cyto-toxicity 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 MAPK11 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 and thus contributing to mHTT accumulation and disease progression. Importantly, knockout of MAPK11 significantly rescues disease-rele-vant 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.

Keywords: PolyQ; high-throughput screening; protein homeostasis; kinasel; positive feedback mechanism; neurodegenera-tive disorders