Post-translational modifications: Regulators of neurodegenerative proteinopathies

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/GSK3 beta, 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 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 Abbreviations: PTMs, Post-translational modifications; NDDs, Neurodegenerative diseases; AD, Alzheimer's disease; PD, Parkinson's disease; ALS, Amyotrophic lateral sclerosis; HD, Huntington's disease; TDP-43, Transactivation response DNA binding protein-43; A beta, beta-amyloid; NFTs, Neurofibrils tangles; SNpc, Substantia nigra pars compacta; polyQ, Polyglutamine; LBs, Lewy bodies; htt, Huntingtin protein; SOD1, Superoxide dismutase 1; UPS, Ubiquitin-proteasome system; CMA, Chaperone mediated autophagy; HSPs, Heat shock proteins; PSEN2, Presenilin-2; IT15, Interesting transcript 15; TARDBP, TAR DNA Binding Protein; NO, Nitric oxide; CK1, Casein kinase 1; GSK-3 beta, Glycogen synthase kinase 3 beta; PKA, Protein kinase A; CDK5, Cyclin-dependent kinase 5; DYRK1A, Dual Specificity Tyrosine Phosphorylation Regulated Kinase 1A; REP, Repressor element of PARKIN; MTS, Mitochondrial targeting sequence; TM, Transmembrane; FUS, Fused in sarcoma; NLS, Nuclear localization sequence; RRMs, RNA recognition motif; NES, Nuclear export sequence; ER, Endoplasmic reticulum; UPR, Unfolded protein response; IRE1 alpha, Inositol-requiring enzyme 1 alpha; PERK, Protein kinase R like endoplasmic reticulum kinase; ATF6 alpha, Activating transcription factor 6 alpha; DR5, Death receptor 5; elF2 alpha, Eukaryotic initiation factor 2 alpha; XBP1, X-box binding protein 1; ASK1-JNK, apoptosis signal-regulating kinase 1/ c-Jun N-terminal kinases; TRAF2, TNF receptor-associated factor 2; PAD4, Protein arginase deaminase 4; SP1, Specificity protein 1; SP2, Specificity protein 2; PARP16, poly ADP ribose polymerase 16; Umf1, ubiquitin fold modifier 1; CHOP, C/EBP homologous protein; ERAD, endoplasmic reticulum-associated degradation; APP, Amyloid precursor protein; PSEN1, Presenilin-1; BACE1, Beta-secretase 1; BiP, Binding immunoglobulin protein; PARKIN, E3 ubiquitin-protein ligase parkin; PINK1, PTEN-induced kinase 1; PDI, Protein disulfide isomerase; GADD34, Growth arrest and DNA damage-inducible protein; DJ1, Protein deglycase; ATFS1, Cyclic AMP-dependent transcription factor;