Immune invasion
Huntington's disease (HD) is an incurable neurodegenerative disease caused by a mutation in the huntingtin gene (htt). Although most of the symptoms of HD are neurological, mutant HTT protein is expressed in non-neural cells, including immune cells. Kwan et al. examined the effects of mutant HTT on the function of immune cells in a mouse model of HD. They found that microglia, the resident macrophages of the CNS, are profoundly impaired in their ability to migrate in HD mice. In the panel on the left, EGFP-expressing microglia (right: normal, left: HD) migrating to a site of laser-induced brain injury were imaged using two-photon laser scanning fluorescence microscopy (video of microglial migration is available here). The panel on the right is an artistic rendering of the migrating microglia provided by the authors. Both microglia and immune cells from the peripheral blood of HD mice and human HD patients exhibited impaired migration. Interestingly, the immune cell defects were apparent prior to the onset of HD symptoms. This study suggests that changes in immune cell function may underlie some of the symptoms of HD.
Related articles
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.
Authors
Wanda Kwan, Ulrike Träger, Dimitrios Davalos, Austin Chou, Jill Bouchard, Ralph Andre, Aaron Miller, Andreas Weiss, Flaviano Giorgini, Christine Cheah, Thomas Möller, Nephi Stella, Katerina Akassoglou, Sarah J. Tabrizi, Paul J. Muchowski
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)