Identification of new neuronal genes capable of regulating systemic proteostasis and aging in C. elegans

• Grant number: 24/18005-3
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: June 01, 2025
• End date: November 30, 2028
• Field of knowledge: Biological Sciences - Physiology - Compared Physiology
• Principal Investigator: Evandro Araújo de Souza
• Grantee: Matheus Antonio Vieira de Castro Ventura
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 22/05851-8 - Mechanisms of regulation of proteostasis in peripheral tissues by the nervous system, AP.GR

Abstract

An organism must be capable of perceiving environmental threats to maximize its chances of survival and the perpetuation of its species. In animals, the central nervous system receives and interprets these environmental signals. Inside cells, the Endoplasmic Reticulum (ER) plays a role in protein secretion pathways and is thus a key player in various stress response contexts. It has been observed that the Unfolded Protein Response of the Endoplasmic Reticulum (UPRER) is involved in several processes of intercellular communication. For instance, it was initially shown in the nematode model Caenorhabditis elegans that both neurons and glial cells regulate the non-autonomous activation of UPRER in distal cells. Although the initial demonstration was done in C. elegans, it is likely that these circuits play a relevant role in behavioral, metabolic, and immune responses in mammals. Studies have shown that neurons in the hypothalamus promote UPRER activation in the liver in response to food perception in mice. However, the molecular mechanisms involved in this signaling remain elusive. In this project, we will use the nematode C. elegans to identify new neuronal regulators of UPRER activation in peripheral tissues by conducting a genetic RNAi (RNA interference) screening in animals expressing a GFP reporter as a UPRER sensor. Candidate genes that regulate UPRER through neuronal mechanisms will be selected using animals with mutations in unc-13-a gene previously characterized as necessary for non-autonomous UPRER activation. Additionally, we intend to use animals with tissue-specific RNAi activity (restricted to either the intestine or neurons) to support our findings. Prioritizing conserved genes, we will seek to validate our RNAi data using mutants and perform functional assays depending on the nature of the genes of interest. Since neuronal activation of UPRER can extend lifespan in C. elegans, we will study the role of these genes in the context of aging and neurodegeneration models. This project has the potential to expand our understanding of the molecular mechanisms involved in the perception of sensory stimuli by neurons and how they transmit these signals to peripheral tissues. Our findings may also lead to the discovery of new genes involved in aging and targets for age-related diseases. (AU)