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.