An Examination of Post-translational Modifications of α-synuclein and its Effects on Parkinson's disease
DOI:
https://doi.org/10.47611/jsrhs.v13i2.6807Keywords:
Parkinson's Disease, Alpha-Synuclein, Post-translational Modifications, Neurodegeneration, Neurodegenerative Diseases, Parkinson's Disease Pathology, Lewy Bodies, Aggregation of alpha synuclein, phosphorylation, truncation, acetylation, ubiquitinationAbstract
Parkinson’s disease (PD) is the second most common degenerative disease of the central nervous system. PD affects millions of people worldwide, so it is critical to research and understand Parkinson’s disease to better help those affected. The exact cause and pathogenesis of PD is unknown, but the aggregation of α-Synuclein into Lewy bodies has been associated with PD. a-Synuclein often goes through post-translational modifications (PTMs). PTMs can affect the shape, localization, function, and activity of proteins like a-Synuclein. PTMs of a-Synuclein can also affect how the protein aggregates. PTMs of α-Synuclein can play a big role in the pathogenesis of PD, and understanding how PTMs affect α-Synuclein is critical in helping forward research that focuses on PD. This paper discusses the effects of various PTMs on α-Synuclein and how they affect the pathogenesis of Parkinson’s Disease.
Downloads
References or Bibliography
“Statistics: Who has Parkinson’s?” Parkinson’s Foundation. Retrieved December 24, 2023, from https://www.parkinson.org/understanding-parkinsons/statistics
Stefanis L. (2011, December 11). α-Synuclein in Parkinson's disease. Cold Spring Harbor perspectives in medicine. Retrieved December 26, 2023, from https://doi.org/10.1101/cshperspect.a009399
Ramazi, S., Zahiri, J. (2021, April 7). Post-translational modifications in proteins: resources, tools and prediction methods. Database. Retrieved December 26, 2023, from https://doi.org/10.1093/database/baab012
Meade, R. M., Fairlie D. P., Mason, J. M. (2019, July 22). Alpha-synuclein structure and Parkinson’s disease – lessons and emerging principles. Mol Neurodegeneration. Retrieved December 28, 2023, from https://doi.org/10.1186/s13024-019-0329-1
Bartels, T., Ahlstrom, L. S., Leftin, A., Kamp, F., Haass, C., Brown, M. F., & Beyer, K. (2010, October 6). The N-terminus of the intrinsically disordered protein α-synuclein triggers membrane binding and helix folding. Biophysical journal. Retrieved January 2, 2024, from https://doi.org/10.1016/j.bpj.2010.06.035
Xu, L., Nussinov, R., & Ma, B. (2016, October 4). Coupling of the non-amyloid-component (NAC) domain and the KTK(E/Q)GV repeats stabilize the α-synuclein fibrils. European journal of medicinal chemistry. Retrieved January 2, 2024, from https://doi.org/10.1016/j.ejmech.2016.01.044
Sorrentino, Z. A., Vijayaraghavan, N., Gorion, K., Riffe, C. J., Strang, K. H., Caldwell, J., Giasson, B. I. (2018, December 7). Physiological C-terminal truncation of α-synuclein potentiates the prion-like formation of pathological inclusions. J Biol Chem. Retrieved January 4, 2024, from https://doi.org/10.1074/jbc.RA118.005603
Kawahata, I., Finkelstein, D. I., & Fukunaga, K. (2022, June 1). Pathogenic Impact of α-Synuclein Phosphorylation and Its Kinases in α-Synucleinopathies. International journal of molecular sciences. Retrieved January 4, 2024, from https://doi.org/10.3390/ijms23116216
Xu, Y., Deng, Y. and Qing, H. (2015, July 2). The phosphorylation of α-synuclein: development and implication for the mechanism and therapy of the Parkinson's disease. J. Neurochem. Retrieved January 4, 2024, from https://doi.org/10.1111/jnc.13234
Chen, W. R., Chen, J. C., Chang, S. Y., Chao, C. T., Wu, Y. R., Chen, C. M., & Chou, C. (2022, December). Phosphorylated α-synuclein in diluted human serum as a biomarker for Parkinson's disease. Biomedical journal. Retrieved January 5, 2024, from https://doi.org/10.1016/j.bj.2021.12.010
Christensen, D. G., Xie, X., Basisty, N., Byrnes, J., McSweeney, S., Schilling, B., & Wolfe, A. J. (2019, July 12). Post-translational Protein Acetylation: An Elegant Mechanism for Bacteria to Dynamically Regulate Metabolic Functions. Frontiers in microbiology. Retrieved January 7, 2024, from https://doi.org/10.3389/fmicb.2019.01604
Xia, C., Tao, Y., Li, M., Che, T., & Qu, J. (2020, July 29). Protein acetylation and deacetylation: An important regulatory modification in gene transcription (Review). Experimental and Therapeutic Medicine. Retrieved January 8, 2024, from https://doi.org/10.3892/etm.2020.9073
Choudhary, C., Kumar, C., Gnad, F., Nielsen, M. L., Rehman, M., Walther, T. C., Olsen, J. V., & Mann, M. (2009, July 16). Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science. Retrieved January 8, 2024, from https://doi.org/10.1126/science.1175371
Bell, R., Vendruscolo M. (2021, July 14). Modulation of the Interactions Between α-Synuclein and Lipid Membranes by Post-translational Modifications. Centre for Misfolding Disease. Retrieved January 9, 2024, from https://doi.org/10.3389/fneur.2021.661117
Bartels, T., Kim, N. C., Luth, E. S., & Selkoe, D. J. (2014, July 30). N-alpha-acetylation of α-synuclein increases its helical folding propensity, GM1 binding specificity and resistance to aggregation. PloS one. Retrieved January 9, 2024, from https://doi.org/10.1371/journal.pone.0103727
Mueller, F., Friese, A., Pathe, C., da Silva, R. C., Rodriguez, K. B., Musacchio, A., & Bange, T. (2021, January 15). Overlap of NatA and IAP substrates implicates N-terminal acetylation in protein stabilization. Science advances. Retrieved January 11, 2024, from https://doi.org/10.1126/sciadv.abc8590
Fortelny, N., Pavlidis, P., & Overall, C. M. (2015, June 15). The path of no return--Truncated protein N-termini and current ignorance of their genesis. Proteomics. Retrieved January 11, 2024, from https://doi.org/10.1002/pmic.201500043
López-Otín, C., & Bond, J. S. (2008, November 7). Proteases: multifunctional enzymes in life and disease. The Journal of biological chemistry. Retrieved January 11, 2024, from https://doi.org/10.1074/jbc.R800035200
DeBoever, C., Tanigawa, Y., Lindholm, M.E. et al. (2018, April 24). Medical relevance of protein-truncating variants across 337,205 individuals in the UK Biobank study. Nat Commun. Retrieved January 12, 2024, from https://doi.org/10.1038/s41467-018-03910-9
Zhang, C., Pei, Y., Zhang, Z., Xu, L., Liu, X., Jiang, L., Pielak, G. J., Zhou, X., Liu, M., & Li, C. (2022, August 9). C-terminal truncation modulates α-Synuclein's cytotoxicity and aggregation by promoting the interactions with membrane and chaperone. Communications biology. Retrieved January 12, 2024, from https://doi.org/10.1038/s42003-022-03768-0
Dufty, B. M., Warner, L. R., Hou, S. T., Jiang, S. X., Gomez-Isla, T., Leenhouts, K. M., Oxford, J. T., Feany, M. B., Masliah, E., & Rohn, T. T. (2007, May). Calpain-cleavage of alpha-synuclein: connecting proteolytic processing to disease-linked aggregation. The American journal of pathology. Retrieved January 13, 2024, from
https://doi.org/10.2353/ajpath.2007.061232
Mannino, M. P., & Hart, G. W. (2022, January 30). The Beginner's Guide to O-GlcNAc: From Nutrient Sensitive Pathway Regulation to Its Impact on the Immune System. Frontiers in immunology. Retrieved January 14, 2024, from https://doi.org/10.3389/fimmu.2022.828648
Levine, P. M., Galesic A., Balana A. T. et al. (2019, January 16). α-Synuclein O-GlcNAcylation alters aggregation and toxicity, revealing certain residues as potential inhibitors of Parkinson’s disease. Proceedings of the National Academy of Sciences. Retrieved January 14, 2024, from https://doi.org/10.1073/pnas.1808845116
Guo HJ., Rahimi N., Tadi P.(2023 Mar 16). Biochemistry, Ubiquitination. StatPearls. Retrieved January 28, 2024, from https://www.ncbi.nlm.nih.gov/books/NBK556052/#:~:text=Ubiquitination%20is%20a%20tightly%20regulated,remove%20unwanted%20or%20damaged%20proteins.
Rott, R., Szargel, R., Shani, V., Hamza, H., Savyon, M., Abd Elghani, F., Bandopadhyay, R., & Engelender, S. (2017, November 27). SUMOylation and ubiquitination reciprocally regulate α-synuclein degradation and pathological aggregation. Proceedings of the National Academy of Sciences of the United States of America. Retrieved February 3, 2024, from https://doi.org/10.1073/pnas.1704351114
Engelender S. (2008, January 18). Ubiquitination of alpha-synuclein and autophagy in Parkinson's disease. Autophagy. Retrieved February 11, 2024, from https://doi.org/10.4161/auto.5604
Wilkinson, K. A., & Henley, J. M. (2010, May 13). Mechanisms, regulation and consequences of protein SUMOylation. The Biochemical journal. Retrieved February 13, 2024, from ttps://doi.org/10.1042/BJ20100158
Krumova, P., Meulmeester, E., Garrido, M., Tirard, M., Hsiao, H. H., Bossis, G., Urlaub, H., Zweckstetter, M., Kügler, S., Melchior, F., Bähr, M., & Weishaupt, J. H. (2011, July 11). Sumoylation inhibits alpha-synuclein aggregation and toxicity. The Journal of cell biology. Retrieved February 25, 2024, from https://doi.org/10.1083/jcb.201010117
Ramalingam, N., & Dettmer, U. (2023, November 13). α-Synuclein serine129 phosphorylation - the physiology of pathology. Molecular neurodegeneration. Retrieved February 29, 2024, from https://doi.org/10.1186/s13024-023-00680-x
Savyon, M., & Engelender, S. (2020, June 25). SUMOylation in α-Synuclein Homeostasis and Pathology. Frontiers in aging neuroscience. Retrieved February 29, 2024, from https://doi.org/10.3389/fnagi.2020.00167
Published
How to Cite
Issue
Section
Copyright (c) 2024 Surya Kapu; Dr. Varkey
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Copyright holder(s) granted JSR a perpetual, non-exclusive license to distriute & display this article.