title: The histone deacetylase HDAC3 is essential for Purkinje cell function, potentially complicating the use of HDAC inhibitors in SCA1.
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 (SCA1(154Q/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 and cognitive deficits of the disease, a complete loss of PC HDAC3 was highly deleterious both behaviorally, with mice showing early onset ataxia, and pathologically, with progressive histologic evidence of degeneration. Inhibition of HDAC3 may yet have a role in SCA1 therapy, but our study provides cautionary evidence that this approach could produce untoward effects. Indeed, the neurotoxic consequences of HDAC3 depletion could prove relevant, wherever pharmacologic inhibition of HDAC3 is being contemplated, in disorders ranging from cancer to neurodegeneration.
authors.affiliation: Davee Department of Neurology and.
authors.forename: Anand
authors.initials: A
authors.lastname: Venkatraman
authors.affiliation: Davee Department of Neurology and.
authors.forename: Yuan-Shih
authors.initials: YS
authors.lastname: Hu
authors.affiliation: Davee Department of Neurology and.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Didonna
authors.affiliation: Davee Department of Neurology and Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Marija
authors.initials: M
authors.lastname: Cvetanovic
authors.affiliation: Davee Department of Neurology and.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Krbanjevic
authors.affiliation: Davee Department of Neurology and.
authors.forename: Patrice
authors.initials: P
authors.lastname: Bilesimo
authors.affiliation: Davee Department of Neurology and Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA and p-opal@northwestern.edu.
authors.forename: Puneet
authors.initials: P
authors.lastname: Opal
mesh_terms: D000818:Animals; D000067696:Ataxin-1; D000067528:Ataxins; D001835:Body Weight; D045744:Cell Line, Tumor; D002531:Cerebellum / Q000473:pathology; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D057809:HEK293 Cells; D057895:Haploinsufficiency; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009043:Motor Activity; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011689:Purkinje Cells / Q000378:metabolism* / Q000473:pathology; D020754:Spinocerebellar Ataxias / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D000099186:Histone Deacetylase 3
chemical_list: D000067696:Ataxin-1; D000067528:Ataxins; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D000099186:Histone Deacetylase 3; C000593749:ATXN1 protein, human; C000593750:Atxn1 protein, mouse