title: 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.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27710, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Bolger
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhao
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Cohen
authors.forename: Chih-Cheng
authors.initials: CC
authors.lastname: Tsai
authors.forename: Tso-Pang
authors.initials: TP
authors.lastname: Yao
mesh_terms: D000818:Animals; D000067696:Ataxin-1; D000067528:Ataxins; D019556:COS Cells; D002531:Cerebellum / Q000166:cytology; D002522:Chlorocebus aethiops; D006655:Histone Deacetylases / Q000378:metabolism; D064326:MEF2 Transcription Factors; D051379:Mice; D008856:Microscopy, Fluorescence; D009154:Mutation; D018006:Myogenic Regulatory Factors / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000502:physiology*; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding; D021381:Protein Transport; D014162:Transfection
chemical_list: D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases