Mutant huntingtin impairs immune cell migration in Huntington disease

Abstract

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.

The choreography of neuroinflammation in Huntington's disease

“…Macrophages isolated from the BACHD mouse model of HD (i.e., containing a bacterial artificial chromosome expressing the full-length human HTT gene containing 97 mixed CAA-CAG repeat expansion in exon 1) exhibit impaired migration to an inflammatory stimulus, and this defect was also seen in blood monocytes from HD patients [87]. It is possible that the observed defect in migration of mutant HTT-expressing macrophages could help explain the absence of innate immune cells infiltration detected in HD brains.…”

“…Importantly, transplantation of HD BM into WT mice was stated to not cause behavioral or neuropathological deficits [90], but these data were not shown and it is unclear whether the efficiency of transplantation in this experiment was comparable between the two genotypes. In addition, this result could be partially explained by the fact that macrophages from mouse models of HD showed defective migratory capacities [87]. Thus, it is possible that the transplanted cells efficiently reconstituted the recipient mice, but did not reach the brain.…”

Actin dynamics shape microglia effector functions

“…Abnormal bundling and accumulation of filamentous actin have also been implicated in the etiopathogenesis of adult-onset neurodegenerative conditions such as Huntington's disease, stroke, severe epileptic seizures, and most notably, Alzheimer's dementia. Both amyloid-b and phosphorylated tau protein promote actin stabilization (Furukawa et al 1997;Endres et al 1999;Fulga et al 2007;Henriques et al 2010;Kwan et al 2012).…”

Microglia in the Physiology and Pathology of Brain

“…Likewise, the transcriptional process in microglia is also altered by mutant huntingtin fragments and this further attests to their ability as possible modulators of neurodegeneration [126]. Concomitantly, mutant huntingtin not only impairs mobility and extension of the microglial processes but also reduces the tissue surveillance efficiency of microglia [127]. Activated microglia exhibit atypical immune reactions via the release of several neurotoxic molecules that contribute to the pathology of HD [128].…”