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Beyond the Glutamine Expansion: Influence of Posttranslational Modifications of Ataxin-1 in the Pathogenesis of Spinocerebellar Ataxia Type 1

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Abstract

Posttranslational modifications are crucial mechanisms that modulate various cellular signaling pathways, and their dysregulation is associated with many human diseases. Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease characterized by progressive ataxia, mild cognitive impairments, difficulty with speaking and swallowing, and respiratory failure. It is caused by the expansion of an unstable CAG trinucleotide repeat encoding a glutamine tract in Ataxin-1 (ATXN1). Although the expansion of the polyglutamine tract is the key determinant of the disease, protein domains outside of the polyglutamine tract and posttranslational modifications of ATXN1 significantly alter the neurotoxicity of SCA1. ATXN1 undergoes several posttranslational modifications, including phosphorylation, ubiquitination, sumoylation, and transglutamination. Such modifications can alter the stability of ATXN1 or its activity in the regulation of target gene expression and therefore contribute to SCA1 toxicity. This review outlines different types of posttranslational modifications in ATXN1 and discusses their potential regulatory mechanisms and effects on SCA1 pathogenesis. Finally, the manipulation of posttranslational modifications as a potential therapeutic approach will be discussed.

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Acknowledgments

We are grateful to the members of the Lim laboratory for their thoughtful comments on the manuscript and Tiffany Todd for editorial input. This work was generously supported by the National Institute of Neurological Disorders and Stroke grant NS064146, National Ataxia Foundation, Brain & Behavior Research Foundation (Formerly NARSAD), Alfred P. Sloan Foundation, Charles H. Hood Foundation, National Multiple Sclerosis Society, and Yale Scholar Award Program to J. Lim.

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  1. Department of Genetics, Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, 295 Congress Avenue, New Haven, CT, 06510, USA

    Hyoungseok Ju, Hiroshi Kokubu & Janghoo Lim

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  1. Hyoungseok Ju
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  2. Hiroshi Kokubu
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  3. Janghoo Lim
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Correspondence to Janghoo Lim.

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Hyoungseok Ju and Hiroshi Kokubu contributed equally to this work.

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Ju, H., Kokubu, H. & Lim, J. Beyond the Glutamine Expansion: Influence of Posttranslational Modifications of Ataxin-1 in the Pathogenesis of Spinocerebellar Ataxia Type 1. Mol Neurobiol 50, 866–874 (2014). https://doi.org/10.1007/s12035-014-8703-z

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