The Effects of Oxidative Stress on RNA Editing with Insight into the Relationship Between Air Pollution and Alzheimer's Disease

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.