title: Histone deacetylase-3 interacts with ataxin-7 and is altered in a spinocerebellar ataxia type 7 mouse model.
abstract: Spinocerebellar ataxia type 7 (SCA7) is caused by a toxic polyglutamine (polyQ) expansion in the N-terminus of the protein ataxin-7. Ataxin-7 has a known function in the histone acetylase complex, Spt/Ada/Gcn5 acetylase (STAGA) chromatin-remodeling complex. We hypothesized that some histone deacetylase (HDAC) family members would impact the posttranslational modification of normal and expanded ataxin-7 and possibly modulate ataxin-7 function or neurotoxicity associated with the polyQ expansion. Interestingly, when we coexpressed each HDAC family member in the presence of ataxin-7 we found that HDAC3 increased the posttranslational modification of normal and expanded ataxin-7. Specifically, HDAC3 stabilized ataxin-7 and increased modification of the protein. Further, HDAC3 physically interacts with ataxin-7. The physical interaction of HDAC3 with normal and polyQ-expanded ataxin-7 affects the toxicity in a polyQ-dependent manner. We detect robust HDAC3 expression in neurons and glia in the cerebellum and an increase in the levels of HDAC3 in SCA7 mice. Consistent with this we found altered lysine acetylation levels and deacetylase activity in the brains of SCA7 transgenic mice. This study implicates HDAC3 and ataxin-7 interaction as a target for therapeutic intervention in SCA7, adding to a growing list of neurodegenerative diseases that may be treated by HDAC inhibitors.
authors.forename: Carlotta E
authors.initials: CE
authors.lastname: Duncan
authors.forename: Mahru C
authors.initials: MC
authors.lastname: An
authors.forename: Theodora
authors.initials: T
authors.lastname: Papanikolaou
authors.forename: Caitlin
authors.initials: C
authors.lastname: Rugani
authors.forename: Cathy
authors.initials: C
authors.lastname: Vitelli
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Blvd, Novato, CA 94945, USA. lellerby@buckinstitute.org.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Ellerby
mesh_terms: D000818:Animals; D000067719:Ataxin-7; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D000099186:Histone Deacetylase 3
chemical_list: D000067719:Ataxin-7; D006655:Histone Deacetylases; D009419:Nerve Tissue Proteins; D000099186:Histone Deacetylase 3; C000593829:ATXN7 protein, human; C000593831:Atxn7 protein, mouse