UCSF

Huntington's disease (HD) is a fatal, incurable neurodegenerative disorder caused by an expanded polyglutamine (polyQ) tract in the protein huntingtin (htt). Recent studies have suggested the potential importance of immune cells in HD pathogenesis. Of particular interest, microglia have early activation and dystrophy in the brains of HD patients and mouse models. HD patients also have increased levels of plasma pro-inflammatory cytokines and chemokines before the onset of motor symptoms that correlate with disease progression. HD patients' monocytes also have increased cytokine levels in response to stimulation. Because htt is ubiquitously expressed, it may directly contribute to the dysfunction of microglia and peripheral immune cells as they have similar origins and functional similarities.

To investigate the effects of mutant htt in immune cells, we first established microglial cell lines that stably express this protein and obtained primary microglia from HD mouse models. We evaluated canonical activation responses and found that microglia expressing mutant htt selectively have increases in pro-inflammatory cytokines and an impairment in stimulus-dependent migration. This migration defect is also present in peripheral immune cells isolated from HD patients, such as monocytes and macrophages. We also observed defective migration of peripheral macrophages towards the site of inflammation upon induction of peritonitis in HD transgenic mice. In the brains of these mice there was also abnormal microglial process extension and retraction, and a delayed response toward laser ablation injury.

Based on our results that mutant htt impairs some immune cell functions and previous evidence of abnormal immune activation in HD, we determined the effects of bone marrow transplantation (BMT) on pathogenesis in vivo. HD donated mice with wild-type (WT) bone marrow had modest but significant improvements of behavioral phenotypes, increased levels of synaptophysin, and normalized levels of peripheral inflammatory cytokines. Our results collectively indicate that mutant htt indeed impairs the function of peripheral and central immune cells in a manner that could be a contributing in a disease-modifying manner to pathogenesis in HD. The cell-autonomous effect of mutant htt in immune cells may also explain the early immune abnormalities in HD. This work has potential implications for HD patients, as there are drugs currently used to treat inflammation that could be tested in HD patients.