Veuthey, Tania et al. (2021) International Worm Meeting "Tyramine modulates the systemic stress response by stimulating the release of intestinal insulin like-peptides (ILPs)"

Rayes, Diego, Alkema, Mark, Giunti, Sebastian, Veuthey, Tania, De Rosa, Maria Jose, Florman, Jeremy

[International Worm Meeting, 2021]

Multicellular organisms trigger a complex and coordinated response against systemic stress. We have recently shown that in C. elegans, the neural stress-hormone tyramine supplies a state-dependent neural switch between acute flight- and long-term environmental-stress responses (De Rosa et al, 2019). Tyramine release during the flight response, stimulates the DAF-2/Insulin/IGF-1 signaling (IIS) pathway and precludes the nuclear translocation of the DAF-16/FOXO transcription factor through the activation of an adrenergic-like receptor TYRA-3 in the intestine. We hypothesize that tyramine stimulates the release of agonist ILPs from the intestine which acts as an autocrine and/or paracrine signal to systemically activate the DAF-2/IIS pathway. To test this hypothesis we are screening ILPs mutants for their resistance to environmental stressors (oxidative and thermal stress). The C. elegans genome encodes 40 ILPs, 28 of which expressed in the intestine. We performed a screening of intestinal peptides described as strong DAF-2 agonist, by silencing individual intestinal ILPs and testing worm resistance to environmental stressors (oxidative and thermal stress). Thus, so far we found that ins-3 and ins-7 mutants are resistant to environmental stress, like tyramine-deficient and tyra-3 mutants. We are further testing whether tyramine directly stimulates the release of these ILPs from the intestine through a Gq-protein mediated signaling pathway. These studies will provide insight into how a neurohormone coordinates systemic cellular stress responses.

Andersen, Natalia et al. (2021) International Worm Meeting "Protective roles of imidazolium salts in C. elegans models of stress and neurodegeneration"

Andersen, Natalia, Silbestri, Gustavo, Veuthey, Tania, De Rosa, Maria Jose, Rayes, Diego

[International Worm Meeting, 2021]

In this study, we aim to evaluate the role of imidazolium salts as antioxidant and anti-aging agents. We synthesized imidazolium salts and use the nematode C. elegans to perform a screening and analyze their ability to improve oxidative stress resistance. We identified a derivate, 1-Mesithyl-3-(3-sulfonatopropyl)imidazolium (MSI), that enhances animal resistance to oxidative stress. As a first approach to delineate its mechanism of action, we evaluated MSI ability to activate transcription factors involved in cytoprotective stress responses, such as the DAF-16/FOXO and SKN-1/Nrf2 pathways. We found that MSI stress protection was not dependent on DAF-16. Nevertheless, we discovered that GST-4 detoxifying enzyme, a downstream effector of SKN-1 transcription factor, is involved in MSI-mediated oxidative stress resistance. Oxidative stress has been largely related with aging and neurodegeneration. To gain further insight into MSI role in proteostasis, we evaluated mobility as an indicator of healthspan in Huntington's, Parkinson's and Alzheimer's disease models. We found that MSI ameliorates mobility rate decline in these proteotoxic models of neurodegenerative diseases. Surprisingly, our results show that MSI did not improve mean lifespan neither in wild-type worms nor in Alzheimer's disease animal models. Overall, our results show a scenario where healthspan seems to be uncoupled to lifespan. Additional research is needed to underpin the mechanism responsible for MSI's protective role.

Zhang J et al. (2019) J Food Biochem "An aqueous polyphenol extract from Rosa rugosa tea has antiaging effects on Caenorhabditis elegans."

Guan Y, Zhang J, Rui X, Dong M, Ma W, Zhang Y, Xiao Y

[J Food Biochem, 2019]

Rosa rugosa aqueous polyphenol (RAP) is a kind of polyphenol from Rosa rugosa flower tea. In this study, the antiaging activities of RAP were studied in the model organism Caenorhabditis elegans. UHPLC-HESI-MS/MS was employed to identify the specific phenolic profile, revealing that there were 23 types of phenolic compounds in RAP and that quercetin glycoside was the principal component. RAP increased the mean lifespan of C. elegans and enhanced the thermotolerance and resistance to oxidative stress of C. elegans in a concentration-dependent manner. Furthermore, RAP showed powerful antioxidant effects in vitro and strong protection against oxidative DNA damage. RAP significantly improved the levels of total superoxide dismutase and total antioxidant capacity of C. elegans. In conclusion, RAP has antiaging effects on C. elegans, which might be related to its powerful antioxidant effects both in vitro and in vivo. PRACTICAL APPLICATIONS: In recent years, chronic diseases associated with aging have had a profound impact on quality of life. Many healthy foods have antiaging properties, especially flower teas, such as those made from Rosa rugosa. Our results indicated that Rosa rugosa tea is good for health and that RAP could potentially be developed as a bioactive product that could be used to combat aging.

Zarkower D et al. (1994) Worm Breeder's Gazette "mab-3 YAC Rescue"

De Bono M, Hodgkin JA, Zarkower D

[Worm Breeder's Gazette, 1994]

mab-3 YAC rescue David Zarkower, Mario de Bono, and Jonathan Hodgkin MRC Laboratory of Molecular Biology, Cambridge, England

Lindblade KA et al. (2007) Am J Trop Med Hyg "Elimination of Onchocercia volvulus transmission in the Santa Rosa focus of Guatemala."

Richards FO, Unnasch TR, Catu E, Lindblade KA, Zea-Flores G, Castro J, Richards J, Punkosdy GA, Porter CH, Cruz-Ortiz N, Arana B, Dominguez A, Rizzo N, Oliva O, Sauerbrey M

[Am J Trop Med Hyg, 2007]

To eliminate transmission of Onchocerca volvulus, semiannual mass treatment with ivermectin (Mectizan; donated by Merck & Co) has been underway in Guatemala since 2000. We applied the 2001 World Health Organization (WHO) elimination criteria in the Santa Rosa focus of onchocerciasis transmission in Guatemala (10,923 persons at risk). No evidence of parasite DNA was found in 2,221 Simulium ochraceum vectors (one-sided 95% confidence interval [CI], 0-0.086%), and no IgG4 antibody positives to recombinant antigen OV16 were found in a sample of 3,232 school children (95% CI, 0-0.009%). We also found no evidence of microfilariae in the anterior segment of the eye in 363 area residents (95% CI, 0-0.08%). Our interpretation of these data, together with historical information, suggest that transmission of O. volvulus is permanently interrupted in Santa Rosa and that ivermectin treatments there can be halted.

Rayes, D. et al. (2019) International Worm Meeting "The flight response impairs cytoprotective mechanisms through neural inhibition of the insulin pathway."

Veuthey, Tania, Blanco, Gabriela, Alkema, Mark, Florman, Jeremy, Andersen, Natalia, Grant, Jeff, Rayes, D., De Rosa, Maria Jose

[International Worm Meeting, 2019]

An animal uses different survival strategies to cope with life-threatening situations. For instance, it can engage in a rapid and energy-demanding "fight-or-flight" response when encountering a predator, or it can induce the gradual and long-lasting activation of highly conserved cytoprotective processes in response to environmental stressors such as hypoxia, heat, oxidative stress, or food shortage. In animals across the evolutionary spectrum the continued activation of the fight-or-flight response weakens the animal's resistance to environmental challenges. In humans, for instance, the recurrent experience of stress in patients that suffer from post-traumatic stress disorder (PTSD) has been associated with decreased antioxidant capacity, accelerated aging and increased susceptibility to metabolic, cardiovascular and infectious diseases. However, the molecular and cellular mechanisms that regulate the trade-off between flight response and long-term stressors are poorly understood. Here we show that repeated induction of the C. elegans flight response shortens lifespan and inhibits conserved cytoprotective mechanisms. The flight response activates neurons that release tyramine, the invertebrate analog of adrenaline/noradrenaline. Tyramine stimulates the DAF-2/Insulin/IGF-1 pathway and precludes the induction of stress response genes by activating an adrenergic-like receptor in the intestine. In contrast, long-term environmental stressors, such as heat or oxidative stress, reduce tyramine release allowing the induction of cytoprotective genes. These findings demonstrate that a neural stress-hormone supplies a state-dependent neural switch between acute flight and long-term environmental stress responses and provides mechanistic insights into how the flight response impairs cellular defense systems and accelerates aging.

Eberhardt AG et al. (2008) Vet Parasitol "The Strongyloides (Nematoda) of sheep and the predominant Strongyloides of cattle form at least two different, genetically isolated populations."

Mayer WE, Eberhardt AG, Streit A, Bonfoh B

[Vet Parasitol, 2008]

Strongyloides sp. (Nematoda) are very wide spread small intestinal parasites of vertebrates that can form a facultative free-living generation. Most authors considered all Strongyloides of farm ruminants to belong to the same species, namely Strongyloides papillosus (Wedl, 1856). Here we show that, at least in southern Germany, the predominant Strongyloides found in cattle and the Strongyloides found in sheep belong to separate, genetically isolated populations. While we did find mixed infections in cattle, one form clearly dominated. This variety, in turn, was never found in sheep, indicating that the two forms have different host preferences. We also present molecular tools for distinguishing the two varieties, and an analysis of their phylogenetic relationship with the human parasite Strongyloides stercoralis and the major laboratory model species Strongyloides ratti. Based on our findings we propose that Strongyloides from sheep and the predominant Strongyloides from cattle should be considered separate species as it had already been proposed by [Brumpt, E., 1921. Recherches sur le determinisme des sexes et de l''evolution des Anguillules parasites (Strongyloides). Comptes rendu hebdomadaires des seances et memoires de la Societe de Biologie et de ses filiales 85, 149-152], but was largely ignored by later authors. For nomenclature, we follow [Brumpt, E., 1921. Recherches sur le determinisme des sexes et de l''evolution des Anguillules parasites (Strongyloides). Comptes rendu hebdomadaires des seances et memoires de la Societe de Biologie et de ses filiales 85, 149-152] and use the name S. papillosus for the Strongyloides of sheep and the name Strongyloides vituli for the predominant Strongyloides of cattle.

De Stasio E et al. (1994) Worm Breeder's Gazette "Mutagenesis of C. elegans Using N-ethyl-N-nitrosourea."

De Stasio E, Stanislaus D, Lephoto C

[Worm Breeder's Gazette, 1994]

Mutagenesis of C. elegans using N-ethyl-N-nitrosourea Elizabeth De Stasio, Dinesh Stanislaus and Catherine Lephoto. Department of Biology, Lawrence University, Appleton, Wl 54911

Sokolowski MB (2002) Nature "Neurobiology: social eating for stress."

Sokolowski MB

[Nature, 2002]

Behavioral ecologists have shown that many animals form social groups in conditions. Neurobiological evidence for this behaviour has now been discovered in the nematode worm, Caenorhabditis elegans. On pages 899 and 925 of this issue, de Bono et al. and Coates and de Bono present striking results on the genetic, molecular and neural mechanisms underlying nematode social feeding. These discoveries provide tantalizing insights into the effects of stress in social groupings.

Platzer K et al. (2018) Am J Hum Genet "De Novo Variants in MAPK8IP3 Cause Intellectual Disability with Variable Brain Anomalies."

Stegmann APA, Bonati MT, Panis B, Smith-Hicks C, Lemke JR, Pepler A, Wilson C, Iascone M, McWalter K, Brasington C, Allen W, Di Donato N, Platzer K, Ramos L, Edwards SL, Jamra R, Gamble CN, Mandel H, Stobe P, Mahida S, Marquardt T, Demmer LA, Miller KG, Falik-Zaccai T, Pinz H, Hellenbroich Y, Sticht H, Kok F, Cho MT, Stumpel CTRM, Shinde DN, Angione KM

[Am J Hum Genet, 2018]

Using exome sequencing, we have identified de novo variants in MAPK8IP3 in 13 unrelated individuals presenting with an overlapping phenotype of mild to severe intellectual disability. The de novo variants comprise six missense variants, three of which are recurrent, and three truncating variants. Brain anomalies such as perisylvian polymicrogyria, cerebral or cerebellar atrophy, and hypoplasia of the corpus callosum were consistent among individuals harboring recurrent de novo missense variants. MAPK8IP3 has been shown to be involved in the retrograde axonal-transport machinery, but many of its specific functions are yet to be elucidated. Using the CRISPR-Cas9 system to target six conserved amino acid positions in Caenorhabditis elegans, we found that two of the six investigated human alterations led to a significantly elevated density of axonal lysosomes, and five variants were associated with adverse locomotion. Reverse-engineering normalized the observed adverse effects back to wild-type levels. Combining genetic, phenotypic, and functional findings, as well as the significant enrichment of de novo variants in MAPK8IP3 within our total cohort of 27,232 individuals who underwent exome sequencing, we implicate de novo variants in MAPK8IP3 as a cause of a neurodevelopmental disorder with intellectual disability and variable brain anomalies.