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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.
AuthorsCarlotta E Duncan, Mahru C An, Theodora Papanikolaou, Caitlin Rugani, Cathy Vitelli, Lisa M Ellerby
JournalMolecular neurodegeneration (Mol Neurodegener) Vol. 8 Pg. 42 (Oct 27 2013) ISSN: 1750-1326 [Electronic] England
PMID24160175 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • ATXN7 protein, human
  • Ataxin-7
  • Atxn7 protein, mouse
  • Nerve Tissue Proteins
  • Histone Deacetylases
  • histone deacetylase 3
Topics
  • Animals
  • Ataxin-7
  • Blotting, Western
  • Brain (metabolism)
  • Disease Models, Animal
  • HEK293 Cells
  • Histone Deacetylases (genetics, metabolism)
  • Humans
  • Immunohistochemistry
  • Immunoprecipitation
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins (genetics, metabolism)
  • Protein Processing, Post-Translational
  • Spinocerebellar Ataxias (genetics, metabolism)
  • Transfection

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