Mutant Huntingtin promotes autonomous microglia activation via myeloid lineage-determining factors

Nat Neurosci. 2014 Apr;17(4):513-21. doi: 10.1038/nn.3668. Epub 2014 Mar 2.


Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an extended polyglutamine repeat in the N terminus of the Huntingtin protein (HTT). Reactive microglia and elevated cytokine levels are observed in the brains of HD patients, but the extent to which neuroinflammation results from extrinsic or cell-autonomous mechanisms in microglia is unknown. Using genome-wide approaches, we found that expression of mutant Huntingtin (mHTT) in microglia promoted cell-autonomous pro-inflammatory transcriptional activation by increasing the expression and transcriptional activities of the myeloid lineage-determining factors PU.1 and C/EBPs. We observed elevated levels of PU.1 and its target genes in the brains of mouse models and individuals with HD. Moreover, mHTT-expressing microglia exhibited an increased capacity to induce neuronal death ex vivo and in vivo in the presence of sterile inflammation. These findings suggest a cell-autonomous basis for enhanced microglia reactivity that may influence non-cell-autonomous HD pathogenesis.

Publication types

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

MeSH terms

  • Animals
  • Cell Death / genetics*
  • Cell Death / physiology
  • DNA Repeat Expansion / genetics
  • Disease Models, Animal
  • Gene Knock-In Techniques
  • Genome-Wide Association Study
  • Humans
  • Huntingtin Protein
  • Huntington Disease / genetics*
  • Huntington Disease / metabolism*
  • Huntington Disease / pathology
  • Inflammation / genetics
  • Inflammation / metabolism
  • Inflammation / pathology
  • Mice
  • Mice, Transgenic
  • Microglia / metabolism*
  • Microglia / pathology
  • Mutation*
  • Myeloid Cells / metabolism
  • Myeloid Cells / pathology
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism*
  • Nuclear Proteins / genetics*


  • HTT protein, human
  • Htt protein, mouse
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Nuclear Proteins

Associated data

  • GEO/GSE54443