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J. Biol. Chem., Vol. 282, Issue 40, 29186-29192, October 5, 2007

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The Neurodegenerative Disease Protein Ataxin-1 Antagonizes the Neuronal Survival Function of Myocyte Enhancer Factor-2^*

Timothy A. Bolger¹, Xuan Zhao¹, Todd J. Cohen, Chih-Cheng Tsai, and Tso-Pang Yao²

From the Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27710 and the Department of Physiology and Biophysics, University of Medicine and Dentistry of New Jersey – Robert Wood Johnson Medical School, Piscataway, New Jersey 08854

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.

Received for publication, May 21, 2007 , and in revised form, July 19, 2007.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains three supplemental figures.

¹ These authors contributed equally to this work.

² A Leukemia and Lymphoma Society Scholar. To whom correspondence should be addressed: Dept. of Pharmacology and Cancer Biology, Box 3813, Duke University Medical Center, Durham, NC 27710. Tel.: 919-613-8654; Fax: 919-668-3954; E-mail: yao00001{at}mc.duke.edu.

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