[
International Worm Meeting,
2019]
A cell needs to maintain protein homeostasis (proteostasis) in order to keep proteins folded over space and time. To ensure proteome fidelity and to buffer proteotoxicity, proteostasis allows cells to rapidly respond to disturbances in the proteome by coordinating protein synthesis and folding, and mitigating protein misfolding by refolding, aggregation and degradation. Proteostasis is managed in a robust and coordinated fashion under the constant surveillance of a collective of proteins known as the proteostasis network (PN). However, the performance of PN is compromised during normal aging, and acute and chronic stress, resulting in the misfolding of proteins and aggregation. Currently, there is limited capacity to quantitatively measure proteostasis buffering capacity (health of proteostasis). In order to probe proteostasis changes and to measure the latent proteostasis buffering capacity in vivo, we will use a Forster-Resonance Energy Transfer (FRET)-based biosensor to sample aggregation states of a 'bait' protein that engages with quality control system (proteostasis network). Upon engagement with quality control proteins, a higher FRET will result. Utilizing information from these FRET changes, we will build a mathematical model to quantify and define the proteostasis buffering capacity under different contexts such as aging, and stress. This has been successfully shown to report the health of protestasis in human cells and hence we would like to establish this biosensor system in intact C. elegans, targeting specific cells and tissues. The outcome of this experiment will allow for an improved understanding on how protein quality control systems keep the proteome folded in time and space, and how dysregulation of this systems contributes to the process of aging and age-dependent diseases.