Unraveling new mechanisms responsible for the cell non-autonomous control of proteostasis in C. elegans

Abstract

The proteome of the cell is challenged throughout life by a variety of factors that generate misfolded proteins, which should be corrected or eliminated to maintain the proteostasis. However, aging overloads the machinery responsible for correcting or degrading these misfolded proteins, which then accumulate in forms of insoluble aggregates that are toxic to the cells. Such protein aggregates, when located in the brain, represent strong risk factors to neurodegenerative diseases, which have become increasingly incidents due to the worldwide increase in life expectancy. miRNAs appear to be excellent candidates in controlling the cellular proteostasis since they selectively inhibit protein synthesis, are expressed in a temporal or tissue-specific manner, are regulated by interventions that prolong lifespan and by aging, and act in cell autonomous and non-autonomous manners in multicellular organisms. Consistent with this hypothesis, we found that the miRNA processing pathway (mainly the enzyme Dicer) controls the susceptibility to age-related proteotoxic stress in a cell non-autonomous manner in the nematode C. elegans. In this study we intend to elaborate the mechanisms through which this proteostatic control takes place, thus contributing to clarify new aspects of the pathophysiology of neurodegenerative diseases. By using the nematode C. elegans we intend to: 1) investigate whether Dicer expression is regulated by proteotoxic stresses, 2) investigate whether silencing Dicer in the whole body or in specific tissues can affect tissue-specific proteostasis, 3) investigate whether Dicer is required to coordinate caloric restriction effects on cell proteostasis, and 4) investigate whether overexpression of Dicer contributes to the formation or the toxicity of protein aggregates during aging. We will use as a tool for this study C. elegans strains that exhibit tissue-specific proteotoxicity such as observed in humans by expression of beta-amiloid peptides or polyglutamine repeats. We will measure their lifespan and paralysis under different conditions where Dicer will be over- or underexpressed. We hope that with this project we will bring new insights onto the role of Dicer and the miRNA processing pathway in the control of proteostasis in multicellular organisms with aims to elucidate new mechanisms to neurodegenerative diseases in humans. (AU)