Mutations in Chemosensory Cilia Cause Resistance to Paraquat in Nematode Caenorhabditis elegans

Abstract

The relationship between oxidative stress and longevity is a matter of concern in various organisms. We isolated mutants resistant to paraquat from nematode Caenorhabditis elegans. One mutant named mev-4 was longlived and showed cross-resistance to heat and Dyf phenotype (defective in dye filling). Genetic and sequence analysis revealed that mev-4 had a nonsense mutation on the che-11 gene, homologues of which are involved in formation of cilia and flagella in other organisms. The paraquat resistance was commonly observed in various Dyf mutants and did not depend on the daf-16 gene, whereas the extension of life span did depend on it. Expression of antioxidant enzyme genes seemed normal. These results suggest that chemosensory neurons are a target of oxidative stress and influence longevity dependent on the daf-16 signaling in C. elegans.The life spans of animals are determined by both environmental and genetic parameters. Accumulating evidence in model organisms demonstrates the importance of genetic approaches with the findings that single gene mutations affect the life span in nematode Caenorhabditis elegans, fruit fly Drosophila melanogaster, and laboratory mice. The key to understanding longevity seems to lie in the network of cell maintenance systems that reduce accumulation of deleterious stresses. The life span of nematodes is controlled by the insulin-like signals from the nervous system (1-3). Such signals also seem to control life span of the fruit fly and mice (4 -7). These results suggest that neuroendocrine pathways in the neurons constitute an important determinant of life span across phylogeny (8 -11).Various lines of evidence show that oxidative stress is a major damaging factor accelerating aging (12, 13). It is invoked by reactive oxygen species (ROS) 1 generated as chemical byproducts of normal cellular metabolisms. Caloric restriction is shown to be beneficial in decreasing the production of ROS in metabolic pathways such as the mitochondrial electron transport system (13). Animals have evolved defense mechanisms against ROS; antioxidant enzymes such as superoxide dismutase (SOD), catalase, and glutathione peroxidase work to eradicate ROS as a first aid (14). However, much remains to be understood as regards the defense mechanisms in diverse tissues of vertebrates. To facilitate understanding of the mechanisms, C. elegans and D. melanogaster are frequently used as a multi-cellular model organism because powerful genetic analysis is possible.In C. elegans, longevity is affected by particular genes involved in dauer larvae formation (15-17), stress resistance (18 -24), mitochondrial function (25-28), caloric restriction (29), reproduction (30 -32), sensory perception (33), neurosecretory function (34), and chromatin silencing (35). Although multiple factors seem to be involved in the longevity, there exist a positive relationship between the capacity to resist oxidative stress and the longevity (12). Nonetheless, the target of oxidative stress is yet to be understood even in this model organis...

Atypical antidepressants extend lifespan of Caenorhabditis elegans by activation of a non‐cell‐autonomous stress response

“…This channel is absent in dye‐filling mutants ( dyf ), such as osm‐3(p802) that lack amphid neurons and, as a result, are resistant to the inhibitory effect of paraquat on development (Fujii et al ., 2004). We confirmed the resistance of osm‐3(p802) larvae to the paraquat‐induced block in development (Fig.…”

GLB‐13 is associated with oxidative stress resistance in caenorhabditis elegans

“…It was reported that resistance to paraquat partially results from the inability to take up paraquat into chemosensory neurons (30). In our experiments, hNgb/EGFP was expressed pan-neuronally.…”

“…In our experiments, hNgb/EGFP was expressed pan-neuronally. Therefore, we tested whether the paraquat resistance of hNgb-Tg worms resulted from a defect in chemosensory neurons (30). Our results showed that chemosensory neurons of N2 and Tg worms were clearly stained (Fig.…”

“…It was reported that growth and metabolism in C. elegans can be regulated by cells in the nervous system (42). Fujii et al reported that neurons are direct targets of paraquat in C. elegans (30). Like in mammals, C. elegans SOD and glutathione are ubiquitously expressed in many tissues (43)(44)(45)(46)(47)(48).…”

“…Unlike these antioxidant enzymes, GLB-13 is only expressed in few neuronal cells, although the evidence that how the signals are processed and integrated with other signals to specify oxidative stress is still unclear. Fujii et al reported that mutations in chemosensory cilia cause resistance to paraquat in C. elegans (30). ROS is a critical pathological factor in the development of many neurological diseases such as neurodegenerative disorders and ischemia (49,50).…”