Shrestha BR et al. (2010) Curr Biol "Neuronal morphogenesis: worms get an EFF in dendritic arborization."

Shrestha BR, Grueber WB

[Curr Biol, 2010]

The development of neuronal dendritic trees involves positive and negative control of growth and branching, as well as modulation of the spacing and orientation of branches. A new study reveals the importance of a membrane fusogen in the dendrite arborization of a pair of highly-branched worm sensory neurons.

Shrestha B et al. (2024) Sci Rep "Folate receptor overexpression induces toxicity in a diet-dependent manner in C. elegans."

Shrestha B, Matilainen O, Tallila M

[Sci Rep, 2024]

Folate receptor (FR) alpha (FOLR1) and beta (FOLR2) are membrane-anchored folate transporters that are expressed at low levels in normal tissues, while their expression is strongly increased in several cancers. Intriguingly, although the function of these receptors in, for example, development and cancer has been studied intensively, their role in aging is still unknown. To address this, we utilized Caenorhabditis elegans, in which FOLR-1 is the sole ortholog of folate receptors. We found that the loss of FOLR-1 does not affect reproduction, physical condition, proteostasis or lifespan, indicating that it is not required for folate transport to maintain health. Interestingly, we found that FOLR-1 is detectably expressed only in uterine-vulval cells, and that the histone-binding protein LIN-53 inhibits its expression in other tissues. Furthermore, whereas knockdown of lin-53 is known to shorten lifespan, we found that the loss of FOLR-1 partially rescues this phenotype, suggesting that elevated folr-1 expression is detrimental for health. Indeed, our data demonstrate that overexpression of folr-1 is toxic, and that this phenotype is dependent on diet. Altogether, this work could serve as a basis for further studies to elucidate the organismal effects of abnormal FR expression in diseases such as cancer.

Shrestha B et al. (2024) Cell Stress Chaperones "Loss of the histone chaperone UNC-85/ASF1 inhibits the epigenome-mediated longevity and modulates the activity of one-carbon metabolism."

Shrestha B, Nieminen AI, Matilainen O

[Cell Stress Chaperones, 2024]

Histone H3/H4 chaperone ASF1 is a conserved factor mediating nucleosomal assembly and disassembly, playing crucial roles in processes such as replication, transcription, and DNA repair. Nevertheless, its involvement in aging has remained unclear. Here, we utilized the model organism Caenorhabditis elegans to demonstrate that the loss of UNC-85, the homolog of ASF1, leads to a shortened lifespan in a multicellular organism. Furthermore, we show that UNC-85 is required for epigenome-mediated longevity, as knockdown of the H3K4 methyltransferase ash-2 does not extend the lifespan of unc-85 mutants. In this context, we found that the longevity-promoting ash-2 RNAi enhances UNC-85 activity by increasing its nuclear localization. Finally, our data indicate that the loss of UNC-85 increases the activity of one-carbon metabolism (OCM), and that downregulation of the OCM component dao-3/MTHFD2 partially rescues the short lifespan of unc-85 mutants. Together, these findings reveal UNC-85/ASF1 as a modulator of the central metabolic pathway and a factor regulating a pro-longevity response, thus shedding light on a mechanism of how nucleosomal maintenance associates with aging.

Liu W et al. (2016) Anticancer Agents Med Chem "Autophagy inhibits apoptosis induced by agrocybe aegerita lectin in hepatocellular carcinoma."

Liu W, Ye X, Sun H, Yu W, Yang Q, Yu G, Jin Y, Shrestha A

[Anticancer Agents Med Chem, 2016]

BACKGROUND: Lectins are carbohydrate-binding proteins that exhibit remarkable anti-tumor activities by inducing apoptotic or autophagic cell death. However, the relationship between apoptosis and autophagy induced by lectins has rarely been reported. Agrocybe aegerita lectin (AAL), a lectin isolated from the fungus Agrocybe aegerita, exerts antitumor activity through apoptosis. METHOD: Growth inhibition of cancer cells by AAL was determined using the CCK-8 kit and the trypan blue assay and was evaluated based on cell morphology. Cell autophagy was studied using western blotting, acridine orange straining, transmission electron microscopy, and transient transfection of pEGFP-LC3 plasmids. We also evaluated AAL-induced autophagy in Caenorhabditis elegans. Apoptosis was studied using flow cytometry. We also identified the antitumor effects of co-treatment of AAL with chloroquine (CQ) in vitro and in vivo. RESULTS: AAL-treated cell lines showed accumulation of microtubule-associated protein light chain 3 II (LC3-II), formation of EGFP-LC3 puncta and acidic autophagic vacuoles (AVOs), and the induction of autophagosomes. Inhibition of autophagy could enhance apoptosis induced by AAL in hepatocellular carcinoma (HCC) cells. Furthermore, AAL and chloroquine were used in a murine in situ HCC model, which revealed that co-therapy (AAL and chloroquine) resulted in an enhanced antitumor effect compared to AAL treatment alone. CONCLUSION: Our findings suggest that inhibition of autophagy exerts a synergistic effect on the antitumor activity of AAL and may be a helpful strategy for reducing the dosage of lectin used in antitumor therapy. The autophagy inhibitor may be a synergist of certain antitumor drugs that can induce both apoptosis and autophagy.

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).

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.

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.

Schaeffer JM et al. (1990) J Antibiot (Tokyo) "Cochlioquinone A, a nematocidal agent which competes for specific [3H]ivermectin binding sites."

Williamson JM, Schaeffer JM, Bergstrom AR, Liesch JM, Goetz MA, Frazier EG

[J Antibiot (Tokyo), 1990]

Cochlioquinone A, isolated from the fungus Helminthosporium sativum, was found to have nematocidal activity. Cochlioquinone A is a competitive inhibitor of specific [3H]ivermectin binding suggesting that cochlioquinone A and ivermectin interact with the same membrane receptor.

Desta IT et al. (2016) J Lab Autom "Detecting and Trapping of a Single C. elegans Worm in a Microfluidic Chip for Automated Microplate Dispensing."

Giakoumidis N, Mustafa N, AlGharibeh N, Orozaliev A, Al-Sharif A, Song YA, Desta IT, Gunsalus KC

[J Lab Autom, 2016]

Microfluidic devices offer new technical possibilities for a precise manipulation of Caenorhabditis elegans due to the comparable length scale. C. elegans is a small, free-living nematode worm that is a popular model system for genetic, genomic, and high-throughput experimental studies of animal development and neurobiology. In this paper, we demonstrate a microfluidic system in polydimethylsiloxane (PDMS) for dispensing of a single C. elegans worm into a 96-well plate. It consists of two PDMS layers, a flow and a control layer. Using five microfluidic pneumatic valves in the control layer, a single worm is trapped upon optical detection with a pair of optical fibers integrated perpendicular to the constriction channel and then dispensed into a microplate well with a dispensing tip attached to a robotic handling system. Due to its simple design and facile fabrication, we expect that our microfluidic chip can be expanded to a multiplexed dispensation system of C. elegans worms for high-throughput drug screening.

Ailion M et al. (2017) Curr Biol "Genetics: Master Regulator or Master of Disguise?"

Malik HS, Ailion M

[Curr Biol, 2017]

The pha-1 gene of Caenorhabditis elegans was originally heralded as a master regulator of organ differentiation. A new study suggests instead that pha-1 actually serves no role in development and instead is a component of a selfish genetic element.