Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly DCE), Delhi 110042, India.
Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly DCE), Delhi 110042, India.
Ageing Res Rev. 2021 Jul;68:101336. doi: 10.1016/j.arr.2021.101336. Epub 2021 Mar 26.
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.
神经退行性疾病（NDDs）的标志性特征之一是细胞环境中聚集的和/或无功能的蛋白质积累。翻译后修饰（PTMs）是NDDs发病机制中无功能蛋白质聚集的重要调节因子。翻译后机制和蛋白质质量控制系统的任何改变，例如分子伴侣、泛素-蛋白酶体系统、自噬-溶酶体降解途径，都会增强错误折叠蛋白质的积累，从而导致神经元功能障碍。翻译后修饰在蛋白质周转率、聚集体积累中起多种作用，还可以帮助降解致病的有毒代谢物。乙酰化、糖基化、磷酸化、泛素化、棕榈酰化、SUMO化、硝化、氧化等翻译后修饰调节蛋白质稳态，包括蛋白质结构、功能和聚集倾向。不同的研究表明，翻译后修饰参与了NDDs发病机制中信号级联反应的调节，如PI3K/Akt/GSK3β、MAPK级联反应、AMPK途径和Wnt信号通路。此外，越来越多的证据表明，用作为抑制剂或激活剂的小分子靶向不同的翻译后修饰，可以逆转错误折叠蛋白质的积累，从而增强神经保护作用。在此，我们简要讨论NDDs中涉及的蛋白质聚集和不同蛋白质的各种结构域结构，指出发生翻译后修饰的关键氨基酸残基。我们还描述了各种翻译后修饰在NDDs信号级联反应和细胞过程中的作用及参与情况。最后，我们阐述了目前对翻译后修饰在神经退行性变中的治疗重要性的理解，以及针对各种翻译后修饰的新兴技术。
