The Curious Case of Copper: Copper’s Novel Stress Response and its Effect on Combined Stress

Abstract

Cells encounter various forms of stress over time–oxidative stress, protein misfolding, DNA damage–and respond by activating specific, well-defined stress response pathways. As we age, the burden of stress increases while our cells’ ability to deal with the resulting damage becomes diminished due to dysregulation of cellular stress response pathways. Copper is a well-studied physiological stressor that is implicated in a variety of age-associated diseases such as cancer, cardiovascular disease, and many more. Though generally considered to be an oxidative stressor, here I describe a novel stress response where copper creates toxicity through an alternate mechanism in C. elegans. I show that this toxicity is independent of the oxidative stress response and several other canonical stress response pathways and is dependent on several genes previously unassociated with copper stress. Next, I describe copper’s protective mechanisms over several other physiological stressors and show that, similar to the individual stress response, this protective mechanism is independent of the oxidative stress response. I select the CuSO4- NaCl combination for further investigation and begin to characterize the genes involved in the C. elegans transcriptional response to the combined stress, identifying several key genes with functions related to immune response, protein processing, and membrane carbohydrate binding activity. In addition to the copper work, I also develop a protocol for longitudinal monitoring of individual worm lifespan, healthspan, and fluorescence in an environment that mimics manual agar lifespan assays. Finally, I propose a set of guidelines for the C. elegans stress response field in order to set standards for experiments and make future work more directly comparable.