The role of Dicer in maintenance of cellular proteostasis in C. elegans

Abstract

The cell's proteome is challenged throughout life by a variety of factors that generate misfolded proteins, which should be corrected or eliminated. However, aging overloads the machinery responsible for correcting and degrading these misfolded proteins that can accumulate forming aggregates. Such protein aggregates, when located in the brain, are strongly correlated with neurodegenerative diseases. Therefore, interventions that slow down the aging are useful to prevent the decline of cellular proteostasis, and, as consequence, prevent the onset of neurodegenerative diseases. Caloric restriction is perhaps the safest, more effective and best proved intervention to combat aging. Mice on caloric restriction can live up to 60 % more than animals feeding ad libitum and are still protected against diseases associated with aging. Moreover, the increased life expectancy in response to caloric restriction has been observed in virtually all species studied so far, from yeast to mammals. In previous studies, our group showed that many components of the miRNAs processing pathway, particularly the enzyme Dicer, are progressively reduced with aging. We have also demonstrated that Dicer expression is positively associated with the effects of caloric restriction in different species. Thus, we propose that interventions that promote miRNA biogenesis can mimic the effects of caloric restriction on delaying the genesis of neurodegenerative diseases. To evaluate Dicer's effects on cellular proteostasis, we will cross C. elegans with gain- or loss-of-function of Dicer with the AM140 strain, which expresses a peptide with 35 glutamine repeats, fused with a yellow fluorescent protein. As these polyglutamine have a strong tendency to aggregate, they compromise the worm's proteostasis, leading to a motor impairment. Therefore, we can monitor and analyze, in a fluorescence stereoscope, the formation of protein aggregates in the offspring of our crosses. We will correlate these aggregates with the movement and lifespan of the worms. We hence intend to propose a new mechanism of control of cellular proteostasis, which could bring insights into new therapies to treat neurodegenerative diseases. (AU)