Mutant huntingtin expression in microglia is neither required nor sufficient to cause the Huntington's disease-like phenotype in BACHD mice

Hum Mol Genet. 2019 May 15;28(10):1661-1670. doi: 10.1093/hmg/ddz009.


Huntington's disease (HD) is caused by a CAG repeat expansion in the HTT gene and is characterized by early and selective striatal neurodegeneration. The huntingtin (HTT) protein is ubiquitously expressed in many tissues and the cellular pathogenesis of the disease is not fully understood. Immune cell dysfunction due to mutant HTT (mHTT) expression and aberrant immune system activation in HD patients suggests that inflammatory processes may contribute to HD pathogenesis. Here we used the BACHD mouse model of HD, which carries a conditional transgene expressing full-length human mHTT, to selectively deplete mHTT expression in myeloid lineage cells, including microglia, and evaluated the effects on HD-related behavior and neuropathology. In the converse experiment, we depleted mHTT expression in the majority of cells in the brain but specifically excluding microglia and again evaluated behavior and neuropathology. In mice with myeloid-specific mHTT-depletion, we observed no significant rescue of any behavioral or neuropathological outcome measures, while neural-specific knockout mice showed significant rescue of body weight, rotarod performance and striatal volume. We conclude that mHTT expression in microglia, though clearly affecting specific aspects of microglia function, does not alter disease pathogenesis in the BACHD mouse model. This may have implications for current or future therapeutic trials testing immune-modulating drugs in HD patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism
  • Brain / pathology
  • Corpus Striatum / metabolism
  • Corpus Striatum / pathology
  • Disease Models, Animal
  • Humans
  • Huntingtin Protein / genetics*
  • Huntington Disease / genetics*
  • Huntington Disease / pathology
  • Mice
  • Mice, Knockout
  • Microglia / metabolism
  • Microglia / pathology
  • Mutant Proteins / genetics*
  • Neurons / metabolism
  • Neurons / pathology
  • Phenotype


  • HTT protein, human
  • Htt protein, mouse
  • Huntingtin Protein
  • Mutant Proteins