Roles of Post-translational Modifications in Spinocerebellar Ataxias

Abstract

Post-translational modifications (PTMs), including phosphorylation, acetylation, ubiquitination, SUMOylation, etc., of proteins can modulate protein properties such as intracellular distribution, activity, stability, aggregation, and interactions. Therefore, PTMs are vital regulatory mechanisms for multiple cellular processes. Spinocerebellar ataxias (SCAs) are hereditary, heterogeneous, neurodegenerative diseases for which the primary manifestation involves ataxia. Because the pathogenesis of most SCAs is correlated with mutant proteins directly or indirectly, the PTMs of disease-related proteins might functionally affect SCA development and represent potential therapeutic interventions. Here, we review multiple PTMs related to disease-causing proteins in SCAs pathogenesis and their effects. Furthermore, we discuss these PTMs as potential targets for treating SCAs and describe translational therapies targeting PTMs that have been published.

Identification and Functional Analysis of Cytokine-Like Protein CLEC-47 in Caenorhabditis elegans

“…The posttranslational modifications are the major differences between prokaryotic and eukaryotic protein expression ( 40 ). Eukaryote-expressed proteins can undertake proteolytic cleavage (like signal peptide removal) and the addition of modifying groups such as acetyl, phosphoryl, glycosyl, and methyl ( 41 ). These modifications play important roles in protein functions.…”

Identifying Therapeutic Targets for Spinocerebellar Ataxia Type 3/Machado–Joseph Disease through Integration of Pathological Biomarkers and Therapeutic Strategies

“…Ataxin-3 has multiple phosphorylation sites (S12, S29, S55, T60, S236, S256, S260, S261, S340, and S352) and specific phosphorylation patterns can decrease or increase aggregation. The phosphorylation sites S12, S29, S55, and T60 are in the Josephin domain responsible for catalytic activity, while S236 is within the first ubiquitin-interacting motif (UIM), S256 and S260/261 are within the second UIM, and S340/S352 is in the third UIM [68]. Phosphorylation at S12 decreases aggregation and reduces protein deubiquitination [69].…”

A Variant in Genes of the NPY System as Modifier Factor of Machado-Joseph Disease in the Chinese Population

“…Although the genetic cause of MJD, abnormal CAG expansion in ATXN3, has been clearly defined for many years (Takiyama et al, 1993;Kawaguchi et al, 1994), the pathogenesis mechanisms of MJD have not been fully elucidated. To date, several different pathways have been identified to be involved in the pathogenesis of MJD: RNA toxicity (Nalavade et al, 2013), abnormal protein aggregation (Seidel et al, 2012), dysregulation of transcription (Raposo et al, 2015), proteolytic cleavage (Weber et al, 2017), post-translational modification (Wan et al, 2018), mitochondrial dysfunction (Ramos et al, 2015), calcium signaling dysregulation (Chen et al, 2008), and damage of neuronal homeostasis (Cunha-Santos et al, 2016). NPY, widely expressed in the central nervous system (CNS), has been implicated in neurogenesis and neuroprotection, playing a crucial role in maintaining neuronal homeostasis (Vezzani et al, 1999).…”