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.
Bibliographical noteFunding Information:
This work was funded by the US National Institutes of Health (grant nos R01 NS062051 and 1R01NS082351); with additional funding from the National Ataxia Foundation and the Brain Research Foundation (P.O.).