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.
Pubmed ID: 29151587 RIS Download
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View all literature mentionsMus musculus with name C57BL/6J from IMSR.
View all literature mentionsThis monoclonal targets Huntingtin Protein, aa 181-810
View all literature mentionsThis monoclonal targets SQSTM1 / p62
View all literature mentionsThis monoclonal targets Mapk14
View all literature mentionsThis monoclonal targets ATF2
View all literature mentionsThis polyclonal targets Phospho-ATF-2 (Thr69/71)
View all literature mentionsThis polyclonal targets HIPK3
View all literature mentionsThis monoclonal targets DARPP32 antibody [EP720Y]
View all literature mentionsThis monoclonal targets Neuronal Class III beta-Tubulin (TUJ1) Purified
View all literature mentionsThis polyclonal targets beta Tubulin
View all literature mentionsThis monoclonal targets SQSTM1 / p62
View all literature mentionsThis monoclonal targets Mapk14
View all literature mentionsThis monoclonal targets ATF2
View all literature mentionsThis polyclonal targets Phospho-ATF-2 (Thr69/71)
View all literature mentionsThis polyclonal targets HIPK3
View all literature mentionsThis monoclonal targets DARPP32 antibody [EP720Y]
View all literature mentionsThis monoclonal targets Neuronal Class III beta-Tubulin (TUJ1) Purified
View all literature mentionsThis polyclonal targets beta Tubulin
View all literature mentionsThis monoclonal targets Huntingtin Protein, aa 181-810
View all literature mentionsThis monoclonal targets Huntingtin Protein, aa 181-810
View all literature mentions