Histone deacetylase-3 interacts with ataxin-7 and is altered in a spinocerebellar ataxia type 7 mouse modelReport as inadecuate




Histone deacetylase-3 interacts with ataxin-7 and is altered in a spinocerebellar ataxia type 7 mouse model - Download this document for free, or read online. Document in PDF available to download.

Molecular Neurodegeneration

, 8:42

First Online: 27 October 2013Received: 22 April 2013Accepted: 09 October 2013

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.

KeywordsHDAC Ataxin-7 Spinocerebellar ataxia type 7 Polyglutamine AbbreviationsSCA7Spinocerebellar ataxia type 7

polyQPolyglutamine

STAGASpt-Ada-Gcn5 acetylase

HDACHistone deacetylase

HATHistone acetyltransferase

TFTCTATA-BP free TAF-containing complex

PTMPosttranslational modification.

Electronic supplementary materialThe online version of this article doi:10.1186-1750-1326-8-42 contains supplementary material, which is available to authorized users.

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Author: Carlotta E Duncan - Mahru C An - Theodora Papanikolaou - Caitlin Rugani - Cathy Vitelli - Lisa M Ellerby

Source: https://link.springer.com/







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