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The neurodegenerative disease protein ataxin-1 antagonizes the neuronal survival function of myocyte enhancer factor-2.

Publication ,  Journal Article
Bolger, TA; Zhao, X; Cohen, TJ; Tsai, C-C; Yao, T-P
Published in: J Biol Chem
October 5, 2007

Ataxin-1 is a neurodegenerative disorder protein whose mutant form causes spinocerebellar ataxia type-1 (SCA1). Evidence suggests that ataxin-1 may function as a transcription repressor. However, neither the importance of this putative transcriptional repression activity in neural cytotoxicity nor the transcriptional targets of ataxin-1 are known. Here we identify the MEF2-HDAC4 transcriptional complex involved in neuron survival as a target of ataxin-1. We show that ataxin-1 binds specifically to histone deacetylase-4 (HDAC4) and MEF2 and colocalizes with them in nuclear inclusion bodies. Significantly, these interactions are greatly reduced by the S776A mutation, which largely abrogates the cytotoxicity of ataxin-1. Supporting the importance of these interactions, we show that wild type ataxin-1 represses MEF2-dependent transcription, whereas the S776A mutant is less potent. Furthermore, overexpression of MEF2 can partially reverse cytotoxicity caused by ataxin-1. Our results identify the MEF2-HDAC4 complex as a target for ataxin-1 transcriptional repression activity and suggest a novel pathogenic mechanism whereby ataxin-1 sequesters and inhibits the neuronal survival factor MEF2.

Duke Scholars

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Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

October 5, 2007

Volume

282

Issue

40

Start / End Page

29186 / 29192

Location

United States

Related Subject Headings

  • Transfection
  • Protein Transport
  • Protein Binding
  • Nuclear Proteins
  • Neurons
  • Neurodegenerative Diseases
  • Nerve Tissue Proteins
  • Myogenic Regulatory Factors
  • Mutation
  • Microscopy, Fluorescence
 

Citation

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Bolger, T. A., Zhao, X., Cohen, T. J., Tsai, C.-C., & Yao, T.-P. (2007). The neurodegenerative disease protein ataxin-1 antagonizes the neuronal survival function of myocyte enhancer factor-2. J Biol Chem, 282(40), 29186–29192. https://doi.org/10.1074/jbc.M704182200
Bolger, Timothy A., Xuan Zhao, Todd J. Cohen, Chih-Cheng Tsai, and Tso-Pang Yao. “The neurodegenerative disease protein ataxin-1 antagonizes the neuronal survival function of myocyte enhancer factor-2.J Biol Chem 282, no. 40 (October 5, 2007): 29186–92. https://doi.org/10.1074/jbc.M704182200.
Bolger TA, Zhao X, Cohen TJ, Tsai C-C, Yao T-P. The neurodegenerative disease protein ataxin-1 antagonizes the neuronal survival function of myocyte enhancer factor-2. J Biol Chem. 2007 Oct 5;282(40):29186–92.
Bolger, Timothy A., et al. “The neurodegenerative disease protein ataxin-1 antagonizes the neuronal survival function of myocyte enhancer factor-2.J Biol Chem, vol. 282, no. 40, Oct. 2007, pp. 29186–92. Pubmed, doi:10.1074/jbc.M704182200.
Bolger TA, Zhao X, Cohen TJ, Tsai C-C, Yao T-P. The neurodegenerative disease protein ataxin-1 antagonizes the neuronal survival function of myocyte enhancer factor-2. J Biol Chem. 2007 Oct 5;282(40):29186–29192.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

October 5, 2007

Volume

282

Issue

40

Start / End Page

29186 / 29192

Location

United States

Related Subject Headings

  • Transfection
  • Protein Transport
  • Protein Binding
  • Nuclear Proteins
  • Neurons
  • Neurodegenerative Diseases
  • Nerve Tissue Proteins
  • Myogenic Regulatory Factors
  • Mutation
  • Microscopy, Fluorescence