Post-translational modifications: Regulators of neurodegenerative proteinopathies

Abstract

One of the hallmark features in the neurodegenerative disorders (NDDs) is the accumulation of aggregated and/or non-functional protein in the cellular milieu. Post-translational modifications (PTMs) are an essential regulator of non-functional protein aggregation in the pathogenesis of NDDs. Any alteration in the post-translational mechanism and the protein quality control system, for instance, molecular chaperone, ubiquitin-proteasome system, autophagy-lysosomal degradation pathway, enhances the accumulation of misfolded protein, which causes neuronal dysfunction. Post-translational modification plays many roles in protein turnover rate, accumulation of aggregate and can also help in the degradation of disease-causing toxic metabolites. PTMs such as acetylation, glycosylation, phosphorylation, ubiquitination, palmitoylation, SUMOylation, nitration, oxidation, and many others regulate protein homeostasis, which includes protein structure, functions and aggregation propensity. Different studies demonstrated the involvement of PTMs in the regulation of signaling cascades such as PI3K/Akt/GSK3β, MAPK cascade, AMPK pathway, and Wnt signaling pathway in the pathogenesis of NDDs. Further, mounting evidence suggests that targeting different PTMs with small chemical molecules, which acts as an inhibitor or activator, reverse misfolded protein accumulation and thus enhances the neuroprotection. Herein, we briefly discuss the protein aggregation and various domain structures of different proteins involved in the NDDs, indicating critical amino acid residues where PTMs occur. We also describe the implementation and involvement of various PTMs on signaling cascade and cellular processes in NDDs. Lastly, we implement our current understanding of the therapeutic importance of PTMs in neurodegeneration, along with emerging techniques targeting various PTMs.

Keywords: Cellular signaling; Neurodegenerative disease; Post-translational modifications; Protein aggregation; Proteinopathies; Unfolded protein response.