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

Abstract

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 <i>Htt</i>^Q111 mice, of <i>Hdac2</i> or <i>Hdac3</i> in medium-spiny striatal neurons that exhibit extensive CAG expansion and exquisite disease vulnerability. Both knockouts moderately attenuated CAG expansion, with <i>Hdac2</i> knockout decreasing nuclear huntingtin pathology. <i>Hdac2</i> knockout resulted in a substantial transcriptional response that included modification of transcriptional dysregulation elicited by the <i>Htt</i>^Q111 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 <i>Htt</i> allele and <i>Hdac2</i> with implications for targeting transcriptional dysregulation in HD.