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

Timothy A Bolger,Xuan Zhao,Todd J Cohen,Chih-Cheng Tsai,Tso-Pang Yao

doi:10.1074/jbc.m704182200

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.

Highlights

Spinocerebellar ataxia-1 (SCA1)3 is an autosomal-dominant neurodegenerative disease that leads to the loss of Purkinje neurons in the cerebellum as well as other neuron subsets [1]
We show that ataxin-1 binds to histone deacetylase-4 (HDAC4) and MEF2 and colocalizes with them in nuclear inclusion bodies
These studies indicate that Histone deacetylase-4 (HDAC4) and MEF2 are regulators of activity-dependent cell death, whether this transcriptional complex is involved in other types of neuron death, such as those associated with neurodegeneration, is not known

Summary

Introduction

Spinocerebellar ataxia-1 (SCA1)3 is an autosomal-dominant neurodegenerative disease that leads to the loss of Purkinje neurons in the cerebellum as well as other neuron subsets [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. These studies indicate that HDAC4 and MEF2 are regulators of activity-dependent cell death, whether this transcriptional complex is involved in other types of neuron death, such as those associated with neurodegeneration, is not known.

Results

Conclusion