Project Summary/Abstract
Huntington’s disease (HD) is an autosomal dominant genetic disorder consisting of an expanded CAG repeat in
exon 1 of the huntingtin gene. The abnormally elongated polyglutamine tract that results in the mutant huntingtin
protein (mHTT) promotes misfolding and the accumulation of multiple pathologic mHTT species. The presence
of mHTT aggregates in the brain leads to progressive striatal and cortical neuronal loss, motor dysfunction,
cognitive disturbances, and eventual death. Activated microglia are evident years before the onset of clinical
symptoms and, similar to their function in other neurodegenerative diseases, are thought to react to disease-
associated neuronal degeneration and damage. In neurodegenerative states, microglia respond to detected
damage by chronically secreting pro-inflammatory cytokines, reactive oxygen species, and other damage
mediators, all of which exacerbate disease progression. Interestingly, neuroinflammatory effects of microglia in
HD are not only secondary to neuronal damage, but the presence of mHTT in microglia itself primes these cells,
leading to an autonomous upregulation of basal pro-inflammatory cytokine production and capacity to cause
neuronal injury. However, the HD field is marked by a paucity of research on the in vivo functional role of microglia
in disease pathogenesis. Our lab previously reported that the sustained inhibition of colony-stimulating factor 1
receptor (CSF1R) eliminates microglia brain-wide in murine models of both health and disease, while subsequent
withdrawal of the inhibitor stimulates repopulation of microglia from CNS-endogenous sources. In a preliminary
study, we found that CSF1R inhibition in the R6/2 transgenic HD mouse model, which expresses exon 1 of the
mutant human huntingtin gene, and nontransgenic mice eliminated = 85% of microglia. This was accompanied
by an amelioration or rescue of several HD-associated behavioral deficits and a reduced accumulation of multiple
species of mHTT in the brain. Separately, our lab recently discovered that CSF1R inhibitor treatment/withdrawal
in bone marrow chimeric mice, whose peripheral immune system was irradiated and reconstituted with donor-
derived cells, stimulates the replacement of virtually all native microglia with infiltrating donor-derived myeloid
cells. Importantly, this allows us to investigate the effects of replacing microglia in the wild-type brain with myeloid
cells from any transgenic line, including HD mice. Therefore, this proposal aims to extend our findings on the
role of microglia in HD by 1) eliminating microglia for 6 months in the long-term zQ175 mouse model of HD
expressing a full-length mutant huntingtin gene and assessing changes in disease-associated behavioral and
pathological phenotypes and 2) utilizing the CSF1R inhibitor/withdrawal paradigm in bone marrow chimeras to
eliminate microglia, transplant zQ175 mouse-derived mHTT-containing myeloid cells into wild-type brains and
subsequently assess alterations in behavior and neuronal viability. Together, this data will elucidate the
therapeutic potential of targeting CSF1R in the clinic with a more relevant mouse model of HD and characterize
the autonomous, as opposed to reactionary, effects of mHTT-containing myeloid cells in the brain.