Project title: Characterizing the Role of Paraoxonase 2 (PON2) in the Brain: Phenotypic Analysis and Modulating Factors
Completed in: 2021 | Faculty advisor: Lucio G. Costa
Paraoxonase 2 (PON2), one of three members of the paraoxonase gene family, is a ubiquitously expressed intracellular antioxidant enzyme. Primarily located at the inner mitochondrial membrane, it is thought to maintain redox homeostasis at the mitochondrial level and support proper cellular function. In the brain, PON2 is expressed highest in dopaminergic regions, such as the striatum and substantia nigra. In-vitro experiments with PON2 deficient primary cells have demonstrated it to be an important antioxidant in the brain, with deficient neural cells more sensitive to oxidative damage. In the general population, common polymorphisms known to affect the enzymatic activity of PON2 have been associated with increased risk for myocardial infarction as well as Alzheimer’s disease, highlighting a direct impact on human health. Despite evidence for PON2 as an important antioxidant in the brain with human health impacts, little attention has focused on the role of PON2 in the brain and what global effects deficiency may have. In my dissertation work, I further characterized PON2 deficiency in the brain to address important knowledge gaps. First, I characterized the developmental expression of PON2, demonstrating that PON2 is differentially expressed over early life development and suggests potential windows of susceptibility to oxidative damage in the developing and aging nervous system when PON2 expression is lowest. Second, I evaluated behavioral endpoints and transcript changes with RNA-Seq of three discrete regions (cerebral cortex, striatum, cerebellum) with PON2 deficiency, finding that PON2 deficient mice have motor deficits and significant changes to many RNA processing pathways. Additionally, PON2 deficiency abolishes sex-specific expression patterns observed in the brain. Building on previous work showing PON2 expression is highest in the dopaminergic regions and may play a role in the dopaminergic system, I compared the expression of key dopaminergic genes in wild type (WT) and PON2 deficient striatal tissue, finding that multiple dopaminergic pathway genes were impacted by PON2 deficiency at the transcript level. Quinpirole, a dopamine receptor 2 (DRD2) agonist, was able to significantly increase the expression of PON2 in-vitro, while fenoldopam, a dopamine receptor 1/5 (DRD1/5) agonist did not, suggesting PON2 plays a role in DRD2-specific signaling. Finally, I collected preliminary data suggesting PON2 deficiency impacts numerous targets relevant to neurodegenerative disease, supporting additional research in the aging nervous system. Taken together, the findings of this dissertation identify that PON2 deficiency has significant impacts on the brain at both a biochemical and phenotypic level. These results address important gaps in the literature regarding PON2 deficiency in the central nervous system and supports further avenues of study to analyze additional pathways and behavioral endpoints, as well as further investigation of PON2 polymorphisms in the population.