Mechanisms of regulation of proteostasis in peripheral tissues by the nervous system

• Grant number: 22/05851-8
• Support Opportunities: Generation Project Research Grant
• Duration: September 01, 2023 - August 31, 2028
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Evandro Araújo de Souza
• Grantee: Evandro Araújo de Souza
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Marcelo Alves da Silva Mori
• Associated scholarship(s): 23/17778-6 - The role of CEPsh glia in the regulation of proteostasis and aging in C. elegans, BP.MS; 23/08316-9 - Mechanisms of regulation of proteostasis in peripheral tissues by the nervous system, BP.GR

Abstract

The ability to perceive the environment is an essential skill for the survival of organisms. In animals, these signals are sensed and transmitted through the nervous system. The endoplasmic reticulum plays a central role in the protein secretion and is a key component in stress responses. Thus, it is not surprising that the Unfolded Protein Response of the endoplasmic reticulum (UPRER) is involved in cell-to-cell communication. Recently, it was shown that both neurons and glial cells can non-autonomously regulate the activation of UPRER in peripheral tissues. Although this phenomenon was initially characterized in C. elegans, this process appears to be conserved in mice, where some types of neurons can regulate UPRER activation in the liver. However, it is still unclear what are the molecular mechanisms involved in this type of signalling. The nematode C. elegans is a valuable model to answer this type of question, due to its genetic toolbox and that is not challenging to monitor the UPRER pathway in different tissues by fluorescence microscopy. To identify regulators of UPRER activation in peripheral tissues, we will perform a genetic screening using RNAi (RNA interference) in animals expressing a GFP reporter as a pathway sensor. Subsequently, we will select which genes act by neuronal mechanisms using animals with mutation in unc-13 - gene previously identified as necessary for the activation of the non-autonomous UPRER. Using CRISPR, we will validate the screening results by mutating genes of interest, prioritizing conserved genes. Since the non-autonomous activation of UPRER leads to increased longevity in C. elegans, we will study the role of these genes in the context of aging and in neurodegeneration models. In parallel, we will investigate the role of glial cells in the regulation of the organism's proteostasis. Previous results show that the absence of CEPsh glia (similar to astrocytes in vertebrates) makes animals more sensitive to drugs that disrupt proteostasis, such as tunicamycin. To understand this phenomenon, we will analyze the gene expression by RNA-seq of a mutant with reduced glial activity. If we are successful, this project will expand our understanding of how the nervous system transmits sensory stimuli to peripheral tissues, what could allow the discovery of new genes involved in aging. The success of this proposal also will allow the establishment of international collaborations and will produce a volume of significant data, paving the way for the consolidation of the research group of the principal investigator in the neurobiology, proteostasis and genetics in C. elegans. (AU)