Franzen da Silva, Aline, Valandro Soares, Marcell, Antunes Soares, Felix, Arantes, Leticia, Obetine, Fabiane, Lopes Machado, Marina, da Silveira, Tassia, Marafiga Cordeiro, Larissa
[
International Worm Meeting,
2021]
Huntington's disease (HD) is an autosomal dominant, progressive neurodegenerative disease. It occurs due to a mutation in the huntingtin gene with an abnormal CAG repeat, leading to a variable length N-terminal polyglutamine chain (poly-Q) which confers toxic functions to mutant Htt leading to neurodegeneration. Rutin is a flavonoid found in plants, buckwheat, some teas and also in apples. Although our previous studies have already indicated that rutin has protective effects in HD's models, more studies are needed to unravel its effects on protein homeostasis and the underlying mechanisms. In our study, we investigated the effects of chronic treatment with rutin in Caenorhabditis elegans model of HD focusing on ASH neurons and antioxidant defense. The synchronized L1 worms were placed on rutin-NGM plates and kept at 20°C. Rutin was added every 24 hours at concentrations of 15, 30, 60 and 120 muM. We assessed octanol response, neuronal polyQ aggregates and dye filling assay. In addition, we analyzed the downstream heat-shock protein-16.2 (HSP-16.2) and superoxide dismutase-3 (SOD-3). Overall, our data demonstrate that chronic rutin treatment maintains the function of ASH neurons in addition to decrease the degeneration of their sensory terminations. The mechanism proposed is antioxidant activity, through the overexpression of antioxidant enzymes and chaperones regulating proteostasis. Our findings provide new evidences about rutin playing a neuroprotective role in C elegans model. In addition to information for treatment strategies for neurodegenerative diseases and other diseases caused by age-related protein aggregation.
[
International Worm Meeting,
2021]
The PIWI/piRNA pathway is a highly conserved small RNA pathway. Central to the pathway is an RNA silencing complex made of an Argonaute protein of the PIWI clade and PIWI-interacting RNAs (piRNAs), which target transposons in animal germlines. In C. elegans, piRNAs also target endogenous protein-coding genes, making the PIWI/piRNA pathway an important regulator of gene expression. C. elegans piRNAs are referred to as 21U RNAs since they are 21 nucleotides long and have a 5' bias for uridine monophosphate. We recently identified a protein complex driving 21U RNA biogenesis, which we named PETISCO (Cordeiro Rodrigues et al., 2019). However, we found that PETISCO can have different functions depending on whether it interacts with the proteins PID-1 (PiRNA Induced silencing Defective) or TOST-1 (Twenty-One U antagoniST). PETISCO:PID-1 complex participates in the 21U RNA biogenesis by interaction and stabilization of the 21U RNA precursors. While being important for gene regulation, the loss of PID-1 is not embryonic lethal. In contrast, PETISCO:TOST-1 is not involved in 21U RNA biogenesis but is nevertheless essential for embryonic development of the subsequent generation (Cordeiro Rodrigues et al., 2019; Zeng et al., 2019). The molecular function of this complex as well as the observed lethality effect is not yet understood. Based on preliminary data, we hypothesize that the PETISCO:TOST-1 complex regulates replication-dependent histones mRNA expression. In this study we want to characterize the PETISCO::TOST-1 complex and dissect its role in embryogenesis. This study would highlight the role of 21U RNA pathway factors in gene expression and C. elegans embryonic development.