The histone deacetylase HDAC3 is essential for Purkinje cell function, potentially complicating the use of HDAC inhibitors in SCA1

Anand Venkatraman, Yuan Shih Hu, Alessandro Didonna, Marija Cvetanovic, Aleksandar Krbanjevic, Patrice Bilesimo, Puneet Opal*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Spinocerebellar ataxia type 1 (SCA1) is an incurable neurodegenerative disease caused by a pathogenic glutamine repeat expansion in the protein ataxin-1 (ATXN1). One likely mechanism mediating pathogenesis is excessive transcriptional repression induced by the expanded ATXN-1. Because ATXN1 binds HDAC3, a Class I histone deacetylase (HDAC) that we have found to be required for ATXN1-induced transcriptional repression, we tested whether genetically depleting HDAC3 improves the phenotype of the SCA1 knock-in mouse (SCA1154Q/2Q), the most physiologically relevant model of SCA1. Given that HDAC3 null mice are embryonic lethal, we used for our analyses a combination of HDAC3 haploinsufficient and Purkinje cell (PC)-specific HDAC3 null mice. Although deleting a single allele of HDAC3 in the context of SCA1 was insufficient to improve cerebellar andcognitive deficits of the disease, a complete loss ofPCHDAC3washighly deleterious both behaviorally, with miceshowing early onset ataxia, and pathologically, with progressive histologic evidence of degeneration. Inhibition ofHDAC3mayyethavearole inSCA1therapy,butourstudy provides cautionary evidencethat this approach could produce untoward effects. Indeed, the neurotoxic consequences ofHDAC3depletion could prove relevant, wherever pharmacologic inhibition of HDAC3 is being contemplated, in disorders ranging from cancer to neurodegeneration.

Original languageEnglish (US)
Article numberddu081
Pages (from-to)3733-3745
Number of pages13
JournalHuman molecular genetics
Volume23
Issue number14
DOIs
StatePublished - Jul 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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