Post-translational modifications: Regulators of neurodegenerative proteinopathies

• Published in: Ageing research reviews Vol. 68; p. 101336
• Main Authors: Gupta, Rohan, Sahu, Mehar, Srivastava, Devesh, Tiwari, Swati, Ambasta, Rashmi K., Kumar, Pravir
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 01.07.2021
• Subjects: Cellular signaling; Neurodegenerative disease; Post-translational modifications; Protein aggregation; Proteinopathies; Unfolded protein response; DNMTs; APP; NF-κβ; PAD4; UBE2D2; PI3K; CMA; UPR; UPS; CHOP; PDK1; RRMs; AD; SREBP; TET-1; DYRK1A; β-TrCP; DKK1; PDR1; AMPK; ULK1; VDAC1; ERK; HDAC; TCF/LEF; UCH-L1; PSEN2; CNS; ATFS1; PSEN1; LRP5/6; FOXO1; HSPs; LAMP2A; Unfolded protein response; GSK-3β; NLS; TAK1; ATF6α; CSMNs; COX2; polyQ; GADD34; ACC; XBP1; Cellular signaling; FUS; DR5; PLK2; IKK; PARP16; DJ1; AGEs; PGC-1α; Umf1; RAGE; NFTs; CDK5; SP2; SP1; TM; Prx2; REP; NES; ATP; Proteinopathies; PAR; Protein aggregation; E-2609; LRRK2; PPIase; ALS; MTS; ADP; DLP-1; Aβ; Dsh; iNOS; PH domain; AMP; PKA; ASK1-JNK; SNpc; TRAF2; IGF-1; MAPK; CaMKKβ; NGF; IT15; ER; ERAD; BACE1; PARKIN; TSC 1/2; TDP-43; TRAF6; Cdks; ROS; PIP3; LBs; mTORC2; mTORC1; PIP2; elF2α; NDDs; NO; USP14; 3-NPA; BCL-xL; CK1; BiP; PERK; ACAT; SNX33; LKB1; Drp1; BCL-2; PDI; CBS; Neurodegenerative disease; AVs; ASK1; FTLD; htt; PTMs; SOD1; PIA2; NAD; PINK1; Post-translational modifications; PD; APC; NEDD4; IRE1α; HD; TARDBP
• ISSN: 1568-1637; 1872-9649
• DOI: 10.1016/j.arr.2021.101336

Post-translational modifications (PTMs) are divided into four groups based on the type of modifications such as the addition of chemical groups (methylation, acetylation, formylation, carboxylation), the addition of polypeptides (ubiquitination, SUMOylation, neddylation), amino acid and structural changes (racemization, citrullination, Isoaspartate), and addition of complex molecules (palmitoylation, glypiation, oxidation, carbonylation). PTMs cause aggregation of misfolded proteins, which further causes an alteration in endoplasmic stress and unfolded protein response. This will deregulate cell-signaling cascades such as PI3K/Akt/GSK3β pathway, p38/MAPK pathway, Wnt signaling cascade, and AMPK transduction pathway. Further, deregulation in the cell-signaling cascade causes impairment in cellular processes such as autophagic degradation, mitochondrial dysfunction, inflammatory response, and cell-cycle deregulation, which increases neurotoxicity and, thus, neuronal cell death. [Display omitted] •Alteration in the protein quality control system causes protein dyshomeostasis.•Accumulation of non-functional protein is the main factor for neurodegenerative disorders (NDDs).•Post-translational modification (PTMs) can also help in the rescue of non-functional proteins.•Different PTMs enzymes serve as a therapeutic target in NDDs and reverse neurological defects. 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.