Sloan, Megan. A et al. (2013) International Worm Meeting "C. elegans as an expression system for drug targets from parasitic nematodes."

Reaves, Barbara. J, Sloan, Megan. A, Wolstenholme, Adrian. J

[International Worm Meeting, 2013]

Many important neglected tropical diseases are caused by parasitic nematodes. Current control programs rely on very few effective anthelmintic drugs and resistance to these may develop. There is therefore a pressing need to find new drugs, which requires a better understanding of parasite genetics and physiology. However studies of parasitic nematodes are complicated and expensive, even when technically feasible, due to the need for passage though infected animals. The development of a system for expressing important parasite genes in C. elegans could make the study of parasitic nematodes much easier and cheaper and would allow us to utilize the powerful genetic resources already available. We have shown that we can express ivermectin target genes, such as avr-14, from the parasite Haemonchus contortus in drug-resistant strains and cause them to revert to drug susceptibility, and also rescue behavioral phenotypes. We have also used this system to demonstrate that novel parasite genes can also act as drug targets. We are now extending these studies to genes encoding subunits of the neuromuscular junction dwelling levamisole-sensitive nicotinic acetylcholine receptor (nAChR) which are well conserved in parasitic nematodes - unc-29 and unc-38. We have cloned unc-29 and unc-38 orthologs from the clade V parasite, H. contortus, and the clade III species, Ascaris suum, downstream of the C. elegans promoters. These constructs are being expressed in unc-29 (ok2450) and unc-38(ok2896) mutants co-transformed with a pmyo-2::GFP marker plasmid to aid detection of transformed worms. The transgenic strains are assessed for levamisole sensitivity and uncoordinated phenotypes.

Goff SP (1999) Cancer Research "Genetic control of programmed cell death in the nematode Caenorhabditis elegans - Introduction."

Goff SP

[Cancer Research, 1999]

It is an honor and a great pleasure to introduce Dr. Robert Horvitz to you as the 1998 recipient of the Alfred Sloan Prize of the General Motors Cancer Research Foundation. Let me begin by telling you a little bit about Bob's

Robert O'Hagan et al. (2004) West Coast Worm Meeting "DEG/ENaCs Form a Sensory Mechanotransduction Channel Complex in C. elegans Touch Receptor Neurons"

Robert O'Hagan, Martin Chalfie, Miriam B Goodman

[West Coast Worm Meeting, 2004]

Transformation of mechanical energy into ionic currents is essential for touch, hearing, and nociception, as well as for control of bodily homeostasis. Members of two ion channel superfamilies (DEG/ENaCs and TRPs) are believed to be sensory mechanotransduction channels; evidence for this, however, remains indirect. In C. elegans , behavioral responses to touch require a set of six touch receptor neurons and at least twelve genes. We have recently shown that four of these genes form an ion channel complex in heterologous cells (1,2). To determine if such channels are directly activated by external force, we recorded from C. elegans touch neurons in vivo . We found that external force evokes rapidly activating mechanoreceptor currents (MRCs) carried mostly by Na + and blocked by amiloride—characteristics consistent with direct mechanical gating of a DEG/ENaC channel. Like mammalian Pacinian corpuscles, C. elegans touch neurons depolarize with both positive and negative changes in external force but not sustained force. Null mutations in the DEG/ENaC gene mec-4 and genes encoding the accessory ion channel subunits MEC-2 and MEC-6 eliminate MRCs. Elimination of touch neuron-specific, large-diameter microtubules by a null mutation in the mec-7 beta-tubulin gene reduces, but does not abolish, MRCs. Our findings provide the first direct evidence linking application of external force to activation of a molecularly-defined metazoan sensory transduction channel. 1. Chelur, D. S., et al. (2002). Nature 420(6916): 669-73. 2. Goodman, M. B., et al. (2002). Nature 415(6875): 1039-42. Supported by an HHMI predoctoral fellowship to RO; an NIGMS grant to MC; and Baxter Foundation, Sloan Foundation, and Terman Faculty Scholarships to MBG.

Quartey MO et al. (2021) Sci Rep "The A(1-38) peptide is a negative regulator of the A(1-42) peptide implicated in Alzheimer disease progression."

Pennington PR, Heistad RM, Nyarko JNK, Barnes JR, Bolanos MAC, Parsons MP, Knudsen KJ, De Carvalho CE, Leary SC, Mousseau DD, Buttigieg J, Maley JM, Quartey MO

[Sci Rep, 2021]

The pool of -Amyloid (A) length variants detected in preclinical and clinical Alzheimer disease (AD) samples suggests a diversity of roles for A peptides. We examined how a naturally occurring variant, e.g. A(1-38), interacts with the AD-related variant, A(1-42), and the predominant physiological variant, A(1-40). Atomic force microscopy, Thioflavin T fluorescence, circular dichroism, dynamic light scattering, and surface plasmon resonance reveal that A(1-38) interacts differently with A(1-40) and A(1-42) and, in general, A(1-38) interferes with the conversion of A(1-42) to a -sheet-rich aggregate. Functionally, A(1-38) reverses the negative impact of A(1-42) on long-term potentiation in acute hippocampal slices and on membrane conductance in primary neurons, and mitigates an A(1-42) phenotype in Caenorhabditis elegans. A(1-38) also reverses any loss of MTT conversion induced by A(1-40) and A(1-42) in HT-22 hippocampal neurons and APOE 4-positive human fibroblasts, although the combination of A(1-38) and A(1-42) inhibits MTT conversion in APOE 4-negative fibroblasts. A greater ratio of soluble A(1-42)/A(1-38) [and A(1-42)/A(1-40)] in autopsied brain extracts correlates with an earlier age-at-death in males (but not females) with a diagnosis of AD. These results suggest that A(1-38) is capable of physically counteracting, potentially in a sex-dependent manner, the neuropathological effects of the AD-relevant A(1-42).

Danielle Thierry-Mieg et al. (2003) Worm Breeder's Gazette "www.wormgenes.org , a new gene centered database"

Vahan Simonyan, Michel Potdevin, Mark Sienkiewicz, Yuji KOHARA, Jean Thierry-Mieg, Danielle Thierry-Mieg, Tadasu SHIN-I

[Worm Breeder's Gazette, 2003]

Wormgenes is a new resource for C.elegans offering a detailed summary about each gene and a powerful query system.

Tangrodchanapong T et al. (2020) Front Pharmacol "Frondoside A Attenuates Amyloid- Proteotoxicity in Transgenic Caenorhabditis elegans by Suppressing Its Formation."

Tangrodchanapong T, Sobhon P, Meemon K

[Front Pharmacol, 2020]

Oligomeric assembly of Amyloid- (A) is the main toxic species that contribute to early cognitive impairment in Alzheimer's patients. Therefore, drugs that reduce the formation of A oligomers could halt the disease progression. In this study, by using transgenic <i>Caenorhabditis elegans</i> model of Alzheimer's disease, we investigated the effects of frondoside A, a well-known sea cucumber <i>Cucumaria frondosa</i> saponin with anti-cancer activity, on A aggregation and proteotoxicity. The results showed that frondoside A at a low concentration of 1 M significantly delayed the worm paralysis caused by A aggregation as compared with control group. In addition, the number of A plaque deposits in transgenic worm tissues was significantly decreased. Frondoside A was more effective in these activities than ginsenoside-Rg3, a comparable ginseng saponin. Immunoblot analysis revealed that the level of small oligomers as well as various high molecular weights of A species in the transgenic <i>C. elegans</i> were significantly reduced upon treatment with frondoside A, whereas the level of A monomers was not altered. This suggested that frondoside A may primarily reduce the level of small oligomeric forms, the most toxic species of A. Frondoside A also protected the worms from oxidative stress and rescued chemotaxis dysfunction in a transgenic strain whose neurons express A. Taken together, these data suggested that low dose of frondoside A could protect against A-induced toxicity by primarily suppressing the formation of A oligomers. Thus, the molecular mechanism of how frondoside A exerts its anti-A aggregation should be studied and elucidated in the future.

Hodgkin JA (1998) International Journal of Developmental Biology "Seven types of pleiotropy."

Hodgkin JA

[International Journal of Developmental Biology, 1998]

Pleiotropy , a situation in which a single gene influences multiple phenotypic tra its, can arise in a variety of ways. This paper discusses possible underlying mechanisms and proposes a classification of the various phenomena involved.

Tuck S (2011) Curr Biol "Extracellular vesicles: budding regulated by a phosphatidylethanolamine translocase."

Tuck S

[Curr Biol, 2011]

Recent work on a Caenorhabditis elegans transmembrane ATPase reveals a central role for the aminophospholipid phosphatidylethanolamine in the production of a class of extracellular vesicles.

Austin L Brown et al. (2004) West Coast Worm Meeting "Accessories to Touch: The Roles of MEC-2 and MEC-6 Studied with Single Channel Recordings."

Miriam B Goodman, Austin L Brown

[West Coast Worm Meeting, 2004]

The sense of touch is still the most enigmatic of the ways organisms learn about their environment. C. elegans is an outstanding organism for the study of sensory mechanotransduction since the response to gentle touch is behaviorally simple and mediated by a set of 6 touch receptor neurons. Genetic analyses have led to the formulation of a molecular model for touch transduction. Central to this model is an ion channel formed by at least four proteins assembled in an unknown stoichiometry: two pore-forming subunits, MEC-4 and MEC-10, and two accessory proteins, MEC-2 and MEC-6. When co-expressed in Xenopus oocytes, MEC-2 and MEC-6 dramatically and synergistically increase current generated by MEC-4/10 ion channels 1,2 . This is consistent with the observation that mutations in any one of the genes encoding these four proteins ruin touch sensation. Moreover, mechanoreceptor currents, recorded in vivo, require intact copies of all four genes (see poster this meeting). Whole-cell recordings in oocytes are unable, however, to distinguish between possible mechanisms for the action of MEC-2 and MEC-6. Each protein must either enhance the single channel conductance, open probability, or some combination of both parameters. Single channel recordings, by contrast, are ideal to differentiate between mechanisms. So far, we have eliminated increases in single channel conductance as an explanation for the effects of MEC-2 and MEC 6 on macroscopic current. We are currently investigating how each accessory protein modulates open probability. 1. Chelur, D. S., et al. (2002). Nature 420(6916): 669-73. 2. Goodman, M. B., et al. (2002). Nature 415(6875): 1039-42. Supported by an AHA Grant-in-Aid, an Alfred P. Sloan and Terman Fellowships to MBG.

Viney ME et al. (2004) Naturwissenschaften "Is dauer pheromone of Caenorhabditis elegans really a pheromone?"

Viney ME, Franks NR

[Naturwissenschaften, 2004]

Animals respond to signals and cues in their environment. The difference between a signal (e.g. a pheromone) and a cue (e.g. a waste product) is that the information content of a signal is subject to natural selection, whereas that of a cue is not. The model free-living nematode Caenorhabditis elegans forms an alternative developmental morph (the dauer larva) in response to a so-called 'dauer pheromone', produced by all worms. We suggest that the production of 'dauer pheromone' has no fitness advantage for an individual worm and therefore we propose that 'dauer pheromone' is not a signal, but a cue. Thus, it should not be called a pheromone.