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

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

doi:10.1038/cr.2017.113

Abstract

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 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 thus contributing to mHTT accumulation and disease progression. Importantly, knockout of MAPK11 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.

Highlights

Neurodegenerative disorders are devastating diseases caused by progressive loss of neurons in the central nervous systems
To reveal druggable modulators of mutant HTT protein (mHTT) levels, we performed an RNA interference (RNAi) screen (Figure 1A) using a focused small interference RNAs (siRNAs) library targeting 2 666 genes expressing proteins that belong to the protein families that are capable of regulating protein levels
The screen was performed in immortalized Huntington’s disease (HD) patient fibroblasts from two independent patients (Q45 and Q68) expressing endogenous full-length human mHTT proteins. mHTT levels were measured by the homologous time-resolved fluorescence (HTRF) assay using the 2B7/MW1 antibody pair which selectively detects mHTT [18] (Supplementary information, Figure S1)

Summary

Introduction

Neurodegenerative disorders are devastating diseases caused by progressive loss of neurons in the central nervous systems. Many types of neurodegenerative disorders share the common feature of the accumulation of misfolded and aggregation-prone proteins, and lowering the levels of these proteins is considered as an appealing therapeutic strategy [2] This strategy is likely to be more effective in inherited monogenetic neurodegenerative diseases, because the casual relationships between the. Recent studies have shown that the level of soluble mHTT is closely related with disease pathology [11,12,13], and lowering soluble mHTT may provide an effective approach to treat HD by ameliorating any downstream toxicity If successful, this strategy is able to modify disease progression, and similar strategies could be applied to other diseases as well [14]. The wtHTT levels and phenotypic outcomes need to be carefully evaluated in any strategy based upon lowering of HTT levels

Methods

Results

Conclusion