[
International Worm Meeting,
2015]
Protein homeostasis is a key facet of longevity, and failure in protein quality control is linked to both age-associated decline and neurodegenerative disorders. One key regulator of protein homeostasis is the Ubiquitin-Proteasome System (UPS), which acts globally to degrade damaged and oxidized proteins. Multiple hormonal and growth factor signaling pathways are implicated in regulating longevity, but the precise interaction between these signaling pathways, global UPS activity, protein homeostasis, and aging is not well understood. We recently demonstrated that components of the Ubiquitin Fusion Degradation (UFD) pathway promote longevity in C. elegans by mediating the polyubiquitination and degradation of damaged and unfolded proteins. We also showed that growth factor signaling modulates the level of global UPS activity at different points during adult maturation and aging, thereby promoting longevity and health. Using an in vivo reporter for UPS activity, we have now performed an RNAi screen (followed by validation with true genetic mutants) for additional regulators of global UPS and identified a dopamine (DA) receptor as a regulator of UPS activity in maturing adults. Here we analyze the detailed molecular interactions between DA signaling and UPS activation in maturing adults by targeting genes involved in DA synthesis, release, reception, and signal transduction. We find that DA is used as an extracellular neurohormone to adjust UPS activity in specific tissues and at specific points in development and aging. Moreover, our recent data shows that specific set of dopamine receptors attribute to this UPS activity regulation in distal tissues and contributes in organismal aging. Molecules involved in this DA-mediated regulation of the UPS are thus potential therapeutic targets for minimizing age-associated decline and neurological disorders.