Taft RJ et al. (2009) Cell Cycle "Evolution, biogenesis and function of promoter-associated RNAs."

Taft RJ, Kaplan CD, Simons C, Mattick JS

[Cell Cycle, 2009]

Transcription initiation is a tightly controlled process that involves chromatin modifications and nucleosome remodelling, transcription factor binding, and the assembly and recruitment of the RNA Polymerase II (RNAPII) complex. Recent studies have reported a diversity of long and short RNAs derived from eukaryotic promoters, which may be involved in transcription regulation. Here we review these species with particular attention to the features and biogenesis of transcription initiation RNAs (tiRNAs), a class of 18 nucleotide small RNA conserved from insects to mammals. We also report and discuss the observation that tiRNAs are not present in plants and are not clearly expressed in the nematode C. elegans. We suggest that tiRNAs may be intimately connected RNAPII backtracking, nucleosome marking, and gene regulation.

Fonte V et al. (2002) Proc Natl Acad Sci U S A "Interaction of intracellular beta amyloid peptide with chaperone proteins."

Taft A, Link CD, Friedman D, Fonte V, Fluet A, Kapulkin V

[Proc Natl Acad Sci U S A, 2002]

Communicated by William B. Wood, University of Colorado, Boulder, CO, May 24, 2002 (received for review March 22, 2002) Expression of the human ss amyloid peptide (Ass) in transgenic Caenorhabditis elegans animals can lead to the formation of intracellular immunoreactive deposits as well as the formation of intracellular amyloid. We have used this model to identify proteins that interact with intracellular Ass in vivo. Mass spectrometry analysis of proteins that specifically coimmunoprecipitate with Ass has identified six likely chaperone proteins: two members of the HSP70 family, three alphaB-crystallin-related small heat shock proteins (HSP-16s), and a putative ortholog of a mammalian small glutamine-rich tetratricopeptide repeat-containing protein proposed to regulate HSP70 function. Quantitative reverse transcription--PCR analysis shows that the small heat shock proteins are also transcriptionally induced by Ass expression. Immunohistochemistry demonstrates that HSP-16 protein closely colocalizes with intracellular Ass in this model. Transgenic animals expressing a nonaggregating Ass variant, a single-chain Ass dimer, show an altered pattern of coimmunoprecipitating proteins and an altered cellular distribution of HSP-16. Double-stranded RNA inhibition of R05F9.10, the putative C. elegans ortholog of the human small glutamine-rich tetratricopeptide-repeat-containing protein (SGT), results in suppression of toxicity associated with Ass expression. These results suggest that chaperone function can play a role in modulating intracellular Ass metabolism and toxicity.

Fonte V et al. (2008) J Biol Chem "Suppression of in vivo beta-amyloid peptide toxicity by overexpression of the HSP-16.2 small chaperone protein."

Forrestal M, Link CD, Wagner E, Kipp DR, Fonte V, Yerg J, Roberts CM, Merin D

[J Biol Chem, 2008]

Expression of the human ss-amyloid peptide (Ass) in a transgenic C. elegans Alzheimer''s disease model leads to the induction of HSP-16 proteins, a family of small heat shock-inducible proteins homologous to vertebrate aB crystallin. These proteins also co-localize and co-immunoprecipitate with Ass in this model (Fonte, V., Kapulkin, V., Taft, A., Fluet, A., Friedman, D. and Link, C. D. (2002) Proc Natl Acad Sci U S A 99, 9439-44). To investigate the molecular basis and biological function of this interaction between HSP-16 and Ass, we generated transgenic C. elegans animals with high level, constitutive expression of HSP-16.2. We find that constitutive expression of wild type, but not mutant, HSP-16.2 partially suppresses Ass toxicity. Wild type Ass 1-42, but not Ass single chain dimer, was observed to become sequestered in HSP-16.2-containing inclusions, indicating a conformation-dependent interaction between HSP-16.2 and Ass in vivo. Constitutive expression of HSP-16.2 could reduce amyloid fibril formation, but did not reduce the overall accumulation of Ass peptide nor alter the pattern of the predominant oligomeric species. Studies with recombinant HSP-16.2 demonstrated that HSP-16.2 can bind directly to Ass in vitro, with a preferential affinity for oligomeric Ass species. This interaction between Ass and HSP-16.2 also influences the formation of Ass oligomers in in vitro assays. These studies are consistent with a model in which small chaperone proteins reduce Ass toxicity by interacting directly with the Ass peptide and altering it''s oligomerization pathways, thereby reducing the formation of a minor toxic species.

Link CD et al. (2003) Neurobiol Aging "Gene expression analysis in a transgenic Caenorhabditis elegans Alzheimer's disease model."

Duke K, Taft A, Wood DE, Kim S, Link CD, Kapulkin V, Fei Q, Sahagan BG

[Neurobiol Aging, 2003]

We have engineered transgenic Caenorhabditis elegans animals to inducibly express the human beta amyloid peptide (Abeta). Gene expression changes resulting from Abeta induction have been monitored by cDNA hybridization to glass slide microarrays containing probes for almost all known or predicted C. elegans genes. Using statistical criteria, we have identified 67 up-regulated and 240 down-regulated genes. Subsets of these regulated genes have been tested and confirmed by quantitative RT-PCR. To investigate whether genes identified in this model system also show gene expression changes in Alzheimer's disease (AD) brain, we have also used quantitative RT-PCR to examine in post-mortem AD brain tissue transcript levels of alphaB-crystallin (CRYAB) and tumor necrosis factor-induced protein 1 (TNFAIP1), human homologs of genes found to be robustly induced in the transgenic C. elegans model. Both CRYAB and TNFAIP1 show increased transcript levels in AD brains, supporting the validity of this approach.

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.