Characterization of Stress Responses in a Drosophila Model of Werner Syndrome

Abstract

As organisms age, their resistance to stress decreases while their risk of disease increases. This can be shown in patients with Werner syndrome (WS), which is a genetic disease characterized by accelerated aging along with increased risk of cancer and metabolic disease. WS is caused by mutations in WRN, a gene involved in DNA replication and repair. Recent research has shown that WRN mutations contribute to multiple hallmarks of aging including genomic instability, telomere attrition, and mitochondrial dysfunction. However, questions remain regarding the onset and effect of stress on early aging. We used a fly model of WS (WRNexoΔ) to investigate stress response during different life stages and found that stress sensitivity varies according to age and stressor. While larvae and young WRNexoΔ adults are not sensitive to exogenous oxidative stress, high antioxidant activity suggests high levels of endogenous oxidative stress. WRNexoΔ adults are sensitive to stress caused by elevated temperature and starvation suggesting abnormalities in energy storage and a possible link to metabolic dysfunction in WS patients. We also observed higher levels of sleep in aged WRNexoΔ adults suggesting an additional adaptive mechanism to protect against age-related stress. We suggest that stress response in WRNexoΔ is multifaceted and evokes a systemic physiological response to protect against cellular damage. These data further validate WRNexoΔ flies as a WS model with which to study mechanisms of early aging and provide a foundation for development of treatments for WS and similar diseases.

A conserved sequence inDrosophilaArgonaute1 mRNA contributes to stress response via inducing miR-999 degradation

“…Accordingly, AGO1 expression is strongly induced in response to stresses such as high concentration of copper, which is known to induce oxidative stress (Figure 7D) 31, 32 . Therefore, we investigated the effects of AGO1 TDMD trigger KO on the lifespan of Drosophila when exposed to hydrogen peroxide, a reactive oxygen species that are routinely used to induce oxidative stress in flies 33, 34 . We fed 9-12 day old flies with 1% sucrose solution containing 4M hydrogen peroxide for 24 hours and returned them to normal food.…”

Screening of Drosophila microRNA-degradation sequences reveals Argonaute1 mRNA’s role in regulating miR-999

“…7d) 33,34 . Therefore, we investigated the effects of AGO1 TDMD trigger KO on the lifespan of Drosophila when exposed to hydrogen peroxide, a reactive oxygen species that are routinely used to induce oxidative stress in flies 35,36 . We fed 9-12-day-old flies with 1% sucrose solution containing 4 M hydrogen peroxide for 24 h and returned them to normal food.…”

Characteristic Hallmarks of Aging and the Impact on Carcinogenesis

“…An optimal model to study aging and the related reduced resistance to stress and augmented risk of disease is the Werner syndrome (WS), a genetic disease caused by mutations in WRN, a gene involved in DNA replication and repair, characterized by accelerated aging, increased risk of cancer and metabolic diseases [94,95]. WRN mutations contribute to multiple hallmarks of aging, including genomic instability, telomere attrition, and mitochondrial dysfunction [96].…”