Histone deacetylase knockouts modify transcription, CAG instability and nuclear pathology in Huntington disease mice.

Somatic expansion of the Huntington's disease (HD) CAG repeat drives the rate of a pathogenic process ultimately resulting in neuronal cell death. Although mechanisms of toxicity are poorly delineated, transcriptional dysregulation is a likely contributor. To identify modifiers that act at the level of CAG expansion and/or downstream pathogenic processes, we tested the impact of genetic knockout, in mice, of or in medium-spiny striatal neurons that exhibit extensive CAG expansion and exquisite disease vulnerability. Both knockouts moderately attenuated CAG expansion, with knockout decreasing nuclear huntingtin pathology. knockout resulted in a substantial transcriptional response that included modification of transcriptional dysregulation elicited by the allele, likely via mechanisms unrelated to instability suppression. Our results identify novel modifiers of different aspects of HD pathogenesis in medium-spiny neurons and highlight a complex relationship between the expanded allele and with implications for targeting transcriptional dysregulation in HD.