PIAS1 Regulates Mutant Huntingtin Accumulation and Huntington's Disease-Associated Phenotypes In Vivo

Neuron. 2016 May 4;90(3):507-20. doi: 10.1016/j.neuron.2016.03.016. Epub 2016 Apr 14.


The disruption of protein quality control networks is central to pathology in Huntington's disease (HD) and other neurodegenerative disorders. The aberrant accumulation of insoluble high-molecular-weight protein complexes containing the Huntingtin (HTT) protein and SUMOylated protein corresponds to disease manifestation. We previously identified an HTT-selective E3 SUMO ligase, PIAS1, that regulates HTT accumulation and SUMO modification in cells. Here we investigated whether PIAS1 modulation in neurons alters HD-associated phenotypes in vivo. Instrastriatal injection of a PIAS1-directed miRNA significantly improved behavioral phenotypes in rapidly progressing mutant HTT (mHTT) fragment R6/2 mice. PIAS1 reduction prevented the accumulation of mHTT and SUMO- and ubiquitin-modified proteins, increased synaptophysin levels, and normalized key inflammatory markers. In contrast, PIAS1 overexpression exacerbated mHTT-associated phenotypes and aberrant protein accumulation. These results confirm the association between aberrant accumulation of expanded polyglutamine-dependent insoluble protein species and pathogenesis, and they link phenotypic benefit to reduction of these species through PIAS1 modulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism*
  • Disease Models, Animal
  • Humans
  • Huntingtin Protein / genetics
  • Huntington Disease / genetics*
  • Mice
  • Mutation / genetics*
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Neurons / metabolism*
  • Nuclear Proteins / metabolism
  • Phenotype
  • Protein Inhibitors of Activated STAT / genetics*
  • Small Ubiquitin-Related Modifier Proteins / genetics*


  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • PIAS1 protein, human
  • Pias1 protein, mouse
  • Protein Inhibitors of Activated STAT
  • Small Ubiquitin-Related Modifier Proteins