Mutant huntingtin impairs immune cell migration in Huntington disease
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
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
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Research Article Neuroscience

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.

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

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Figure 3

Microglia show defective basal process dynamics and delayed responses to focal laser ablation in the cortex of BACHD mice in vivo.

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Microglia show defective basal process dynamics and delayed responses to...
Microglia from WT;Cx3cr1GFP/+ (WT) or BACHDTg/+;Cx3cr1GFP/+ (BACHD) mice were imaged in vivo using 2-photon microscopy at 12–18 months of age. (A) Baseline time-lapse imaging of microglia demonstrated reduced extension and increased retraction of microglial processes over 10 minutes in BACHDTg/+;Cx3cr1GFP/+ compared with WT;Cx3cr1GFP/+ control mice. *P < 0.05 (t test). (B) Tissue ablation with a laser (white zone in center) results in rapid extension of microglial processes toward the site of injury in WT;Cx3cr1GFP/+ mice. In contrast, microglia from BACHDTg/+;Cx3cr1GFP/+ mice show a delayed response over a 60-minute period. (C) Quantification of process extension toward the site of laser ablation. P < 0.001 (2-way ANOVA). (D) The average velocity of process extension is significantly decreased in microglia from BACHDTg/+Cx3cr1GFP/+ mice over a 45-minute period. *P < 0.05 (t test). Values are mean ± SEM. n = 4–5 mice. Scale bar: 10 μm.