Unravelling the mechanisms of longevity control by mobile RNAs

Author(s)

Henrique Camara

• Document type: Doctoral Thesis
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia
• Defense date: 2021-06-18

Examining board members

Fernanda Marques da Cunha; Murilo Vieira Geraldo; Henrique Marques Souza; Alexandre Hiroaki Kihara

• Advisor: Marcelo Alves da Silva Mori

Abstract

Non-coding RNAs such as miRNAs and siRNAs have an important role in gene regulation in different cell types, contributing to the health of the organism. In addition to their role as an autonomous regulator of cellular function, non-coding RNAs are also secreted and regulate the function of distant target cells. However, the transport mechanisms of these RNAs and the physiological consequences of this regulation are not yet fully understood. In C. elegans, the Systemic RNAi Defective (SID) protein family was related to the secretion and incorporation of extracellular RNAs. In a previous project, we evaluated mutant worms for the different SID proteins and observed changes in several phenotypes such as egg laying, development time, resistance to stress and aging. These were more evident in mutants for SID-1 and SID-3, fundamental proteins for internalization of extracellular RNAs. In the present thesis I have expanded this evaluation, using new mutant alleles for sid-1 and sid-3, as well as models of transgenic tissue-specific expression of sid-1. I confirmed the deleterious effects of the sid-3 (ok973) mutation with the sid-3 (tm342) allele. On the other hand, the sid-1 (qt2) and sid-1 (qt9) alleles did not show the defects previously observed with sid-1 (pk3321), which was revealed to result from off-target mutations in the worm used. However, I observed that the tissue-specific expression of SID-1 in the intestine, muscle or neuron affects the nematode's lifespan. This modulation of lifespan depends on the animal's diet and with the systemic RNAi and miRNA pathways. Finally, the neuronal expression of SID-1 induces the locomotor coil phenotype in worms, suggesting changes in neuronal function. Collectively, the data indicate that changing the function of RNA transport machinery has profound and diverse effects on the physiology of C. elegans. These effects suggest that extracellular RNAs are used to regulate different biological functions and that RNA transport activity must be kept under fine control in order to avoid cellular dysfunction (AU)

• FAPESP's process: 17/01339-2 - Uncovering mechanisms of longevity mediated by mobile RNAs
• Grantee: Henrique Camara
• Support Opportunities: Scholarships in Brazil - Doctorate