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

Cell Res. 2017 Dec;27(12):1441-1465. doi: 10.1038/cr.2017.113. Epub 2017 Oct 13.

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.

MeSH terms

  • Animals
  • Cells, Cultured
  • Disease Models, Animal*
  • Humans
  • Huntingtin Protein / genetics*
  • Huntingtin Protein / metabolism
  • Huntington Disease / genetics*
  • Huntington Disease / metabolism
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinase 11 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 11 / deficiency
  • Mitogen-Activated Protein Kinase 11 / metabolism
  • Mutation*
  • Phenotype
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / metabolism

Substances

  • HTT protein, human
  • Huntingtin Protein
  • Intracellular Signaling Peptides and Proteins
  • HIPK3 protein, human
  • Protein-Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinase 11