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

Abstract

Post-translational 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 post-translational modifications of ATXN1 significantly alter the neurotoxicity of SCA1. ATXN1 undergoes several post-translational 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 post-translational modifications in ATXN1 and discusses their potential regulatory mechanisms and effects on SCA1 pathogenesis. Finally, the manipulation of post-translational modifications as a potential therapeutic approach will be discussed.

Altered RNA metabolism due to a homozygousRBM7mutation in a patient with spinal motor neuropathy

“…ATXN1 is known to be linked to the pathogenesis of spinocerebellar ataxia type 1 (42). Extended polyQ stretch within the protein causes toxicity and neurodegeneration of PCs, the nuclei of the brainstem cranial nerves, the inferior olives, and the spinocerebellar tracts (43,44). ATXN1 is important for differentiation of PCs in mouse (45).…”

Roles of Post-translational Modifications in Spinocerebellar Ataxias

“…In addition, S776 phosphorylation inhibits ATXN1 localisation to the nucleus by masking the nuclear localisation signal, which also prevents dephosphorylation ( Lai et al, 2011 ). S776 phosphorylation is also essential for the formation of the ATXN1-CIC complex, which is vital for ATXN1 maintenance and stabilisation; thus, this complex might be relevant to SCA1 disease progression ( Ju et al, 2014 ). Binding to U2AF65, a constitutive component of the spliceosome, is impeded but not eliminated by the phosphorylation of S776, and this reduces ATXN1 binding to the large spliceosome machinery, leaving ATXN1 conformationally extended and vulnerable to self-association and aggregation ( Menon et al, 2012 ).…”

“…These modifications mostly arise from covalently attaching functional groups to specific amino acid residues including phosphate, acetate, and other chemical moieties, while another modification called proteolytic cleavage results from removing or separating specific portions of proteins ( Karve and Cheema, 2011 ; Matos et al, 2017 ) ( Table 1 ). PTMs, such as phosphorylation, acetylation, ubiquitination, SUMOylation, and proteolytic cleavage, can modulate the turnover, localisation, activity, and interaction of proteins ( Ju et al, 2014 ). Thus, PTMs play pivotal roles in regulating multiple cellular pathways to further modulate pathogenesis in a number of diseases.…”

Spinocerebellar ataxia 1: case and cohort-based studies in India

“…ATXN1 also binds RNA in a manner inversely proportional to its polyQ length 27 . Additionally, ATXN1 undergoes several posttranslational modifications, including phosphorylation, ubiquitination, sumoylation and transglutamination 28 . Such modifications can alter the stability of ATXN1 or its activity in the regulation of target gene expression and, therefore contribute to SCA1 toxicity 28 .…”

“…Additionally, ATXN1 undergoes several posttranslational modifications, including phosphorylation, ubiquitination, sumoylation and transglutamination 28 . Such modifications can alter the stability of ATXN1 or its activity in the regulation of target gene expression and, therefore contribute to SCA1 toxicity 28 . Studies in the cerebella of SCA1 mice and patients have shown transcriptional dysregulation of several intracellular calcium signalling genes prior to the onset of disease phenotypes, indicating that cellular and transcriptional changes indeed antedate neuronal death [29][30][31] .…”