The Effects of Oxidative Stress on RNA Editing with Insight into the Relationship Between Air Pollution and Alzheimer's Disease
Article Sidebar
Main Article Content
Abstract
Human interactions with the environment today add pressure on the world’s resources and ecosystems, which in turn harm human health. Many anthropogenic environmental changes, including climate change, biodiversity loss, and pollution, have accelerated morbidity and mortality. Research across multiple countries have found correlations between anthropogenic air pollution exposure and neurological degeneration, particularly with Alzheimer’s disease (AD). RNA editing induced by oxidative stress is one possible mechanism in which air pollution increases the risk of AD. To study this further, RNA adenosine-to-inosine (A-to-I) alterations were analyzed to identify a mechanism linking air pollution to neurological degeneration. These alterations occur in RNA, most prevalently in the central nervous system (CNS). Adenosine deaminase acting on RNA (ADAR) enzymes mediate A-to-I alterations and are essential for mammalian development and survival. ADAR mediated alterations have been associated with AD and the A-to-I occurrence frequency may increase in polluted environments that trigger increased oxidative stress. To test this possibility, wildtype (WT) and ADAR knockout (adr-2(-) Caenorhabditis elegans in their first larval (L1) developmental stage were exposed to juglone solution for 0, 15, and 60 minute experimental settings. For the two worm strains, WT and adr-2(-), the 0 minute treatment was the control, the 15 minute treatment represented acute oxidative stress exposure, and the 60 minute treatment represented chronic exposure. RNA was extracted from both groups and quantitative Real Time PCR (qRT-PCR) was used to measure the expression of gst-4, an Alzheimer’s associated gene (sel-12), and adr-2 normalized to the expression of gpd-3, the housekeeping gene that corrected for systemic errors. The gst-4 gene expression confirmed that oxidative stress occurred. Lack of adr-2 gene significantly decreased sel-12 expression at acute exposure, but adr-2 gene expression in WT worms did not significantly change across treatments. It remains to be determined whether oxidative stress impacts RNA editing of target mRNAs. Future studies are needed to explore the role of adr-2 in promoting sel-12 expression.
Downloads
Article Details
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Authors who publish with this journal agree to the following terms:
- Ownership of the copyright shall remain with the Author, subject to IUJUR’s use and the rights granted by the Creative Commons license assigned by the Author. A Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) license will be applied to the published work unless otherwise indicated in the Student Author Contract. The CC BY-NC 4.0 license (https://creativecommons.org/licenses/by-nc/4.0/) lets others remix, tweak, and build upon the published Work non-commercially, and although the new works must also acknowledge the original IUJUR publication and be noncommercial, they don’t have to license their derivative works on the same terms.Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).
References
Altun, Z. F., & Hall, D. H. (2009). Introduction to C. elegans Anatomy.
Anantharaman, A., Tripathi, V., Khan, A., Yoon, J.-H., Singh, D. K., Gholamalamdari, O., … Prasanth, K. V. (2017). ADAR2 regulates RNA stability by modifying access of decay-promoting RNA-binding proteins. Nucleic Acids Research, 45(7), 4189–4201. https://doi.org/10.1093/nar/gkw1304
Annese, A., Manzari, C., Lionetti, C., Picardi, E., Horner, D. S., Chiara3, M., … D’Erchia, A. M. (2018). Whole transcriptome profling of Late-Onset Alzheimer’s Disease patients provides insights into the molecular changes involved in the disease. Scientific Reports, 8(4282). https://doi.org/10.1038/s41598-018-22701-2
Association, A., Ph.D., W. T., & Bleiler, L. (2013). 2013 Alzheimer’s disease facts and figures. The Journal of The Alzheimer’s Associatino, 208–245.
Bahn, J. H., Ahn, J., Lin, X., Zhang, Q., Lee, J.-H., Civelek, M., & Xiao, X. (2015). Genomic analysis of ADAR1 binding and its involvement in multiple RNA processing pathways. Nature Communications, 6(1), 6355. https://doi.org/10.1038/ncomms7355
Cai, Y., An, S. S. A., & Kim, S. (2015). Mutations in presenilin 2 and its implications in Alzheimer’s disease and other dementia-associated disorders. Clinical Interventions in Aging, 10, 1163–1172. https://doi.org/10.2147/CIA.S85808
Calvo-Rodriguez, M., Hou, S. S., Snyder, A. C., Kharitonova, E. K., Russ, A. N., Das, S., … Bacskai, B. J. (2020). Increased mitochondrial calcium levels associated with neuronal death in a mouse model of Alzheimer’s disease. Nature Communications, 11(1), 1–17. https://doi.org/10.1038/s41467-020-16074-2
Carey, I. M., Anderson, H. R., Atkinson, R. W., Beevers, S. D., Cook, D. G., Strachan, D. P., … Kelly, F. J. (2018). Are noise and air pollution related to the incidence of dementia? A cohort study in London, England. BMJ Open, 8(9), 1–11. https://doi.org/10.1136/bmjopen-2018-022404
Chen, H., Kwong, J. rey C., Copes, R., Tu, K., Villeneuve, P. J., Donkelaar, A. van, … Burnett, R. T. (2017). Living near major roads and the incidence of dementia, Parkinson’s disease, and multiple sclerosis: a population-based cohort study. The Lancet, 389, 718–26. Retrieved from https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736%2816%2932399-6.pdf
Christofi, T., & Zaravinos, A. (2019). RNA editing in the forefront of epitranscriptomics and human health. Journal of Translational Medicine, 17(1), 319. https://doi.org/10.1186/s12967-019-2071-4
Dall, T. M., Gallo, P. D., Chakrabarti, R., West, T., Semilla, A. P., & Storm, M. V. (2013). An Aging Population And Growing Disease Burden Will Require A Large And Specialized Health Care Workforce By 2025. The Care Span, 11, 2013–2020. Retrieved from 10.1377/hlthaff.2013.0714%0AHEALTH AFFAIRS 32,
Gardner, O. K., Wang, L., Van Booven, D., Whitehead, P. L., Hamilton-Nelson, K. L., Adams, L. D., … Griswold, A. J. (2019). RNA editing alterations in a multi-ethnic Alzheimer disease cohort converge on immune and endocytic molecular pathways. Human Molecular Genetics, 28(18), 3053–3061. https://doi.org/10.1093/hmg/ddz110
Haghani, A., Dalton, H. M., Safi, N., Sioutas, F. S. C., Morgan, T. E., Finch, C. E., & Curran, S. P. (2019). Air Pollution Alters Caenorhabditis elegans Development and Lifespan: Responses to Traffic-Related Nanoparticulate Matter. Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 74(8), 1189–1197. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625599/
Hartner, J. C., Schmittwolf, C., Kispert, A., Müller, A. M., Higuchi, M., & Seeburg, P. H. (2004). Liver Disintegration in the Mouse Embryo Caused by Deficiency in the RNA-editing Enzyme ADAR1. Journal of Biological Chemistry, 279(6), 4894–4902. Retrieved from https://doi.org/10.1074/jbc.M311347200
Higuchi, M., Maas, S., Single, F. N., Hartner, J., Rozov, A., Burnashev, N., … Seeburg, P. H. (2000). Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2. Nature, 406(6791), 78–81. https://doi.org/10.1038/35017558
Hundley, H. A., Krauchuk, A. A., & Bass, B. L. (2008). C. elegans and H. sapiens mRNAs with edited 3’ UTRs are present on polysomes. RNA (New York, N.Y.), 14(10), 2050–2060. https://doi.org/10.1261/rna.1165008
Ivanov, I. P., Gurvich, O. L., Gesteland, R. F., & Atkins, J. F. (2013). Recoding: Site- or mRNA-Specific Alteration of Genetic Readout Utilized for Gene Expression. Madame Curie Bioscience Database. Austin, TX.
Jordan, J. (2020). 65 and Older Population Grows Rapidly as Baby Boomers Age. United States Census Bureau. Retrieved from https://www.census.gov/newsroom/press-releases/2020/65-older-population-grows.html
Kaletta, T., & Hengartner, M. O. (2006). Finding function in novel targets: C. elegans as a model organism. Nature Reviews Drug Discovery, 5(5), 387–399. https://doi.org/10.1038/nrd2031
Khermesh, K., D’Erchia, A. M., Barak, M., Annese, A., Wachtel, C., Levanon, E. Y., … Eisenberg, E. (2016). Reduced levels of protein recoding by A-to-I RNA editing in Alzheimer’s disease. RNA, 22(2), 290–302. https://doi.org/10.1261/rna.054627.115
Liguori, I., Russo, G., Curcio, F., Bulli, G., Aran, L., Della-Morte, D., … Abete, P. (2018). Oxidative stress, aging, and diseases. Clinical Interventions in Aging, 13, 757–772. https://doi.org/10.2147/CIA.S158513
Lobo, V., Patil, A., Phatak, A., & Chandra, N. (2010). Free radicals, antioxidants and functional foods: Impact on human health. Pharmacognosy Reviews, 4(8), 118–126. https://doi.org/10.4103/0973-7847.70902
Lodish, H., Berk, A., Zipursky, S., & et al. (2000). The Three Roles of RNA in Protein Synthesis. In Molecular Cell Biology. New York: W. H. Freeman. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK21603/
Lodovici, M., & Bigagli, E. (2011). Oxidative Stress and Air Pollution Exposure. Journal of Toxicology, 2011. https://doi.org/10.1155/2011/487074
Maas, S., Kawahara, Y., Tamburro, K. M., & Nishikura, K. (2006). A-to-I RNA editing and human disease. RNA Biology, 3(1), 1–9. https://doi.org/10.4161/rna.3.1.2495
National Center for Health Statistics. (2020). Underlying Cause of Death 1999-2010. CDC WONDER Online Database, Released 2012. Retrieved from http://wonder.cdc.gov/ucd-icd10.html
Nishikura, K. (2016). A-to-I editing of coding and non-coding RNAs by ADARs. Nature Reviews. Molecular Cell Biology, 17(2), 83–96. https://doi.org/10.1038/nrm.2015.4
Palladino, M. J., Keegan, L. P., O’Connell, M. A., & Reenan, R. A. (2000). A-to-I pre-mRNA editing in Drosophila is primarily involved in adult nervous system function and integrity. Cell, 102(4), 437–449. https://doi.org/10.1016/S0092-8674(00)00049-0
Park, S.-K., Tedesco, P. M., & Johnson, T. E. (2009). Oxidative stress and longevity in Caenorhabditis elegans as mediated by SKN-1. Aging Cell, 8(3), 258–269. https://doi.org/10.1111/j.1474-9726.2009.00473.x
PSEN2 presenilin 2 [Homo sapiens (human)]. (2021). Bethesda, MD. Retrieved from https://www.ncbi.nlm.nih.gov/gene/5664
Rajendren, S., Dhakal, A., Vadlamani, P., Townsend, J., Deffit, S. N., & Hundley, H. A. (2021). Profiling neural editomes reveals a molecular mechanism to regulate RNA editing during development. Genome Research, 31(1), 27–39. https://doi.org/10.1101/gr.267575.120
Sarasija, S., Laboy, J. T., Ashkavand, Z., Bonner, J., Tang, Y., & Norman, K. R. (2018). Presenilin mutations deregulate mitochondrial Ca2+ homeostasis and metabolic activity causing neurodegeneration in Caenorhabditis elegans. ELife, 1–30. https://doi.org/https://doi.org/10.7554/eLife.33052
Senchuk, M. M., Dues, D. J., & Raamsdonk, J. M. Van. (2017). Measuring Oxidative Stress in Caenorhabditis elegans: Paraquat and Juglone Sensitivity Assays. Bio-Protocol, 7(1). https://doi.org/10.21769/BioProtoc.2086
Steingraber, S. (2010). Living Downstream (2nd ed.). Philadelphia: First Da Capo Press.
Tonkin, L. A., Saccomanno, L., Morse, D. P., Brodigan, T., Krause, M., & Bas, B. L. (2002). RNA editing by ADARs is important for normal behavior in Caenorhabditis elegans. The EMBO Journal, 21, 6025–6035. Retrieved from https://doi.org/10.1093/emboj/cdf607
Wang, I. X., So, E., Devlin, J. L., Zhao, Y., Wu, M., & Cheung, V. G. (2013). ADAR Regulates RNA Editing, Transcript Stability, and Gene Expression. Cell Reports, 5(3), 849–860. https://doi.org/10.1016/j.celrep.2013.10.002
Younan, D., Petkus, A. J., Widaman, K. F., Wang, X., Casanova, R., Espeland, M. A., … Chen, J.-C. (2020). Particulate matter and episodic memory decline mediated by early neuroanatomic biomarkers of Alzheimer’s disease. Brain, 143(1), 289–302. https://doi.org/10.1093/brain/awz348
Zhang, X., Chen, X., & Zhang, X. (2018). The impact of exposure to air pollution on cognitive performance. Proceedings of the National Academy of Sciences, 115(37), 9193–9197. Retrieved from https://doi.org/10.1073/pnas.1809474115