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

First Author  Kovalenko M Year  2020
Journal  Elife Volume  9
PubMed ID  32990597 Mgi Jnum  J:298667
Mgi Id  MGI:6477066 Doi  10.7554/eLife.55911
Citation  Kovalenko M, et al. (2020) Histone deacetylase knockouts modify transcription, CAG instability and nuclear pathology in Huntington disease mice. Elife 9:e55911
abstractText  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 Htt(Q111) mice, of Hdac2 or Hdac3 in medium-spiny striatal neurons that exhibit extensive CAG expansion and exquisite disease vulnerability. Both knockouts moderately attenuated CAG expansion, with Hdac2 knockout decreasing nuclear huntingtin pathology. Hdac2 knockout resulted in a substantial transcriptional response that included modification of transcriptional dysregulation elicited by the Htt(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 Htt allele and Hdac2 with implications for targeting transcriptional dysregulation in HD.
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