Post-translational modifications: Regulators of neurodegenerative proteinopathies |
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| Affiliation: | 1. Team Bio-PeroxIL ‘Biochemistry of the Peroxisome, Inflammation and Lipid Metabolism’ (EA 7270), University Bourgogne Franche-Comté (UBFC), Inserm, Dijon, France;2. Bioactive Molecules Research Laboratory, Doctoral School of Sciences and Technologies, Faculty of Sciences, Lebanese University, Fanar, Lebanon;3. University Monastir, Faculty of Medicine, LR12ES05, Lab-NAFS ‘Nutrition - Functional Food & Vascular Health’, Monastir, Tunisia;4. University Tunis El Manar, Laboratory of Onco-Hematology (LR05ES05), Faculty of Medicine, 1007 Tunis, Tunisia;5. University Sousse, Faculty of Medicine, Sousse, Tunisia;6. University Abderrahmane Mira of Béjaia, Department of Food Sciences, Faculty of Natural and Life Sciences, Laboratory of Biophysics, Biochemistry, Biomathematics and Scientometry (3BS), Béjaia, Algeria;7. LCPMC-A2, ICPM, Dept of Chemistry, Univ. Lorraine, Metz Technopôle, Metz, France;8. Team OCS, Institute of Molecular Chemistry of University of Burgundy (ICMUB UMR CNRS 6302), University of Bourgogne Franche-Comté, Dijon, France;9. Plateforme de Lipidomique – Univ. Bourgogne Inserm UMR1231, LabEx LipSTIC, UFR des Sciences de Santé, Dijon, France;10. Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi, India;11. Sabinsa Corporation, 20 Lake Drive, East Windsor, NJ, USA;12. Department of Pharmacognosy, University of Vienna, Vienna, Austria;13. Ludwig Boltzmann Institute for Digital Health and Patient Safety, Medical University of Vienna, Vienna, Austria;14. Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, Jastrzebiec, Poland;15. Institute of Neurobiology, Bulgarian Academy of Sciences, Sofia, Bulgaria;p. Department of Physiology, School of Medicine, University College Cork, Cork, Ireland;q. Laboratory of Biochemistry and Neurosciences, Department of Biology, University Hassan I, 26000 Settat, Morocco;1. Robson DNA Science Centre, Arnie Charbonneau Cancer Institute, Calgary, Alberta, T2N 4N1, Canada;2. Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, T2N 4N1, Canada;3. Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, T2N 4N1, Canada;1. State Key Laboratory of Medical Genetics and School of Life Sciences, Central South University, Changsha, Hunan 410078, China;2. Shanghai Institute of Appllied Physics, Chinese Academy of Sciences, Shanghai 201800, China;3. Department of Pharmacology, Hubei University of Science and Technology, Xianning, Hubei 437100, China;1. Discipline of Exercise Science, College of Science, Health, Engineering and Education, Murdoch University, 90 South St, Murdoch, Western Australia, Australia;2. Australian Alzheimer’s Research Foundation, Sarich Neuroscience Research Institute Building, 8 Verdun St, Nedlands, Western Australia, Australia;3. Curtin Health Innovation Research Institute, Sarich Neuroscience Research Institute Building, 8 Verdun St, Nedlands, Western Australia, Australia;4. Perron Institute for Neurological and Translational Science, Sarich Neuroscience Research Institute Building, 8 Verdun St, Nedlands, Western Australia, Australia;5. School of Biological Sciences, The University of Western Australia, 35 Stirling Hwy, Crawley, Western Australia, Australia;6. Centre for Healthy Ageing, Murdoch University, 90 South St, Murdoch, Western Australia, Australia;7. Murdoch Applied Sports Science Laboratory, Murdoch University, 90 South St, Murdoch, Western Australia, Australia;8. School of Medical and Health Sciences, Edith Cowan University, 270 Joondalup Dr, Joondalup, Western Australia, Australia;9. School of Psychological Science, University of Western Australia, 35 Stirling Hwy, Crawley, Western Australia, Australia;10. Department of Biomedical Sciences, Macquarie University, Balaclava Rd, Macquarie Park, New South Wales, Australia |
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| 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. |
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| Keywords: | Post-translational modifications Neurodegenerative disease Proteinopathies Protein aggregation Unfolded protein response Cellular signaling |
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