Mutant huntingtin impairs immune cell migration in Huntington disease

J Clin Invest. 2012 Dec;122(12):4737-47. doi: 10.1172/JCI64484. Epub 2012 Nov 19.


In Huntington disease (HD), immune cells are activated before symptoms arise; however, it is unclear how the expression of mutant huntingtin (htt) compromises the normal functions of immune cells. Here we report that primary microglia from early postnatal HD mice were profoundly impaired in their migration to chemotactic stimuli, and expression of a mutant htt fragment in microglial cell lines was sufficient to reproduce these deficits. Microglia expressing mutant htt had a retarded response to a laser-induced brain injury in vivo. Leukocyte recruitment was defective upon induction of peritonitis in HD mice at early disease stages and was normalized upon genetic deletion of mutant htt in immune cells. Migration was also strongly impaired in peripheral immune cells from pre-manifest human HD patients. Defective actin remodeling in immune cells expressing mutant htt likely contributed to their migration deficit. Our results suggest that these functional changes may contribute to immune dysfunction and neurodegeneration in HD, and may have implications for other polyglutamine expansion diseases in which mutant proteins are ubiquitously expressed.

Publication types

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

MeSH terms

  • Actin Depolymerizing Factors / metabolism
  • Actins / metabolism
  • Adenosine Triphosphate / physiology
  • Animals
  • Cell Surface Extensions / metabolism
  • Cells, Cultured
  • Chemotaxis*
  • Complement C5a / physiology
  • Humans
  • Huntingtin Protein
  • Huntington Disease / genetics*
  • Huntington Disease / immunology
  • Huntington Disease / pathology
  • Macrophages / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microglia / cytology
  • Microglia / physiology*
  • Monocytes / physiology
  • Mutation
  • Myeloid Cells / cytology
  • Myeloid Cells / physiology*
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Peritoneum / pathology
  • Thioglycolates / pharmacology
  • Time-Lapse Imaging


  • Actin Depolymerizing Factors
  • Actins
  • HTT protein, human
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Thioglycolates
  • Complement C5a
  • Adenosine Triphosphate