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

Abstract	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.
Authors	Timothy A Bolger, Xuan Zhao, Todd J Cohen, Chih-Cheng Tsai, Tso-Pang Yao
Journal	The Journal of biological chemistry (J Biol Chem) Vol. 282 Issue 40 Pg. 29186-92 (Oct 05 2007) ISSN: 0021-9258 [Print] United States
PMID	17646162 (Publication Type: Journal Article)
Chemical References	Ataxin-1 Ataxins Atxn1 protein, mouse MEF2 Transcription Factors Myogenic Regulatory Factors Nerve Tissue Proteins Nuclear Proteins Hdac5 protein, mouse Histone Deacetylases
Topics	Animals Ataxin-1 Ataxins COS Cells Cerebellum (cytology) Chlorocebus aethiops Histone Deacetylases (metabolism) MEF2 Transcription Factors Mice Microscopy, Fluorescence Mutation Myogenic Regulatory Factors (metabolism) Nerve Tissue Proteins (metabolism, physiology) Neurodegenerative Diseases (metabolism) Neurons (metabolism) Nuclear Proteins (metabolism, physiology) Protein Binding Protein Transport Transfection

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!