Glutathione reductase protects Caenorhabditis elegans against proteotoxic stress

Abstract

Resumen del trabajo presentado al VI Spanish Worm Meeting, celebrado en Valencia del 9 al 10 de marzo de 2017.In contrast to mammals, the thioredoxin system is dispensable in the model organism Caenorhabditis elegans as double mutants lacking both cytoplasmic and mitochondrial thioredoxin reductases are fully viable and have no discernable phenotype. To test if the glutathione/glutaredoxin system is the main determinant for redox homeostasis in this organism, we have recently characterized the C. elegans gsr-1 gene that encodes both cytoplasmic and mitochondrial isoforms of glutathione reductase. We have found that gsr-1 mutants are sensitized to oxidative stress, have fragmented mitochondria and compromised mitochondrial function, are short-lived and have an aberrant distribution of the interphasic chromatin in the nuclear periphery of the embryonic cells. These data support the notion that the glutathione pathway is the major determinant for redox homeostasis in C. elegans. Protein aggregation is a major hallmark of many neurodegenerative disorders such as Alzheimer, Parkinson or Huntington diseases. Proteotoxic stress, generated by aggregation-prone proteins, causes profound perturbations of redox homeostasis in both C. elegans and mammalian models. However, it is not known whether redox homeostasis impacts proteostasis. Interestingly, when the gsr-1 mutation was introduced in worm models of proteotoxicity caused by aggregation-prone proteins, we found that the phenotypes associated to proteostasis maintenance were severely impaired. This protective eect of GSR-1 is independent of the nature of the aggregating protein as well as the tissue where it is expressed. Furthermore, we were able to pharmacologically recapitulate these phenotypes using inhibitors of GSH synthesis, GSSG reduction and GSH depletors, further confirming a protective role of GSH in proteostasis maintenance. We will present recent data aimed to identify the molecular players and signaling pathways involved in this protective role of GSR-1 and GSH in proteostasis.Peer Reviewe