scholarly journals Caenorhabditis elegans model for admixed proteinopathy of Huntington’s and Alzheimer-type

2019 ◽  
Author(s):  
Wadim J. Kapulkin
Keyword(s):  
Caenorhabditis Elegans ◽  
Clinical Symptoms ◽  
Fluorescent Proteins ◽  
Amyloid Formation ◽  
Dependent Manner ◽  
Huntington's Chorea ◽  
C Elegans ◽  
Pathogenic Variants ◽  
Models Of Disease

ABSTRACTFormation of proteinaceous deposits composed of abnormally aggregated proteins characterizes a range of pathological conditions. Proteinaceous inclusions detected in the neurodegenerative conditions such Huntington’s chorea (HD) and Alzheimer’s disease (AD) are often referred as pathognomic and regarded as causally implicated. Despite of differences in aetiology and underlying genetics, rare cases of combined HD and AD were reported and described as admixed proteinopathies. Mixed proteopathies are characterized by the co-occurrence of at least two types of abnormal aggregation-prone variants; pathological deposition of proteinaceous inclusions might however, affect different cell populations. Here, combining plaques derived from human ß-amyloid with mutant HTT-like polyglutamine inclusions in a cell-autonomous manner, we report on the Caenorhabditis elegans model for admixed proteinopathy of Alzheimer’s and Huntington’s type. We show both types of intracellular foci are formed in vivo: non-amyloidic extended polyglutamine derived inclusions and distinguish those from the presence of mature ß- amyloid fibers. We found that polyglutamines expanded above pathogenic threshold and ß-amyloid act synergistically to promote the progression of proteotoxicity in a temperature dependent manner. We further, implicate the hsp-1 (the predominant C. elegans chaperone interacting with ER-routed Aß42) modulate the proteotoxic insults observed in combined proteopathy model. Our results demonstrate how the in vivo model of admixed proteopathy could be utilized to probe for human pathogenic variants confined to the same cellular type. In that perspective expanded aggregation-prone polyglutamines appended with fluorescent proteins could be regarded as ‘pathogenic probes’ useful in the proteotoxicity assays i.e. involving ß-amyloid and possibly other comparable models of disease-associated aggregation prone variants.We anticipate models of combined proteopathies will be informative regarding the underlying pathogenesis and provide the sensitized background for sophisticated screening. For example the combinatorial effects of multiple pathogenic aggregation-prone variants could be tested against mutant backgrounds and pharmacological compounds. Furthermore, we surmise the postulated synergistic actions might explain some of the overlaps in observed progression of clinical symptoms in HD and AD. We also formulate the conjecture regarding the polyQ containing proteins as a contributing factor in degenerative conditions associated with increased ß-amyloid formation and deposition.

A Cuticle Collagen Encoded by the lon-3 Gene May Be a Target of TGF-β Signaling in Determining Caenorhabditis elegans Body Shape

Genetics ◽  
2002 ◽  
Vol 162 (4) ◽  
pp. 1631-1639
Author(s):  
Yo Suzuki ◽  
Gail A Morris ◽  
Min Han ◽  
William B Wood
Keyword(s):  
Caenorhabditis Elegans ◽  
Body Shape ◽  
Small Body ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Cellular Mechanisms ◽  
C Elegans ◽  
Gene Expression Analyses ◽  
Dose Dependent

Abstract The signaling pathway initiated by the TGF-β family member DBL-1 in Caenorhabditis elegans controls body shape in a dose-dependent manner. Loss-of-function (lf) mutations in the dbl-1 gene cause a short, small body (Sma phenotype), whereas overexpression of dbl-1 causes a long body (Lon phenotype). To understand the cellular mechanisms underlying these phenotypes, we have isolated suppressors of the Sma phenotype resulting from a dbl-1(lf) mutation. Two of these suppressors are mutations in the lon-3 gene, of which four additional alleles are known. We show that lon-3 encodes a collagen that is a component of the C. elegans cuticle. Genetic and reporter-gene expression analyses suggest that lon-3 is involved in determination of body shape and is post-transcriptionally regulated by the dbl-1 pathway. These results support the possibility that TGF-β signaling controls C. elegans body shape by regulating cuticle composition.

scholarly journals Caenorhabditis elegans as an in vivo Model to Assess Amphetamine Tolerance

2021 ◽  
pp. 1-9
Author(s):  
Dayana Torres Valladares ◽  
Sirisha Kudumala ◽  
Murad Hossain ◽  
Lucia Carvelli
Keyword(s):  
Caenorhabditis Elegans ◽  
Molecular Mechanisms ◽  
Drugs Of Abuse ◽  
Genetic Model ◽  
In Vivo Model ◽  
C Elegans ◽  
Hyperactivity Disorder ◽  
In Vitro Data

Amphetamine is a potent psychostimulant also used to treat attention deficit/hyperactivity disorder and narcolepsy. In vivo and in vitro data have demonstrated that amphetamine increases the amount of extra synaptic dopamine by both inhibiting reuptake and promoting efflux of dopamine through the dopamine transporter. Previous studies have shown that chronic use of amphetamine causes tolerance to the drug. Thus, since the molecular mechanisms underlying tolerance to amphetamine are still unknown, an animal model to identify the neurochemical mechanisms associated with drug tolerance is greatly needed. Here we took advantage of a unique behavior caused by amphetamine in <i>Caenorhabditis elegans</i> to investigate whether this simple, but powerful, genetic model develops tolerance following repeated exposure to amphetamine. We found that at least 3 treatments with 0.5 mM amphetamine were necessary to see a reduction in the amphetamine-induced behavior and, thus, to promote tolerance. Moreover, we found that, after intervals of 60/90 minutes between treatments, animals were more likely to exhibit tolerance than animals that underwent 10-minute intervals between treatments. Taken together, our results show that <i>C. elegans</i> is a suitable system to study tolerance to drugs of abuse such as amphetamines.

Transfer and tissue-specific accumulation of components in embryos of Caenorhabditis elegans and dolichura: in vivo analysis with a low-cost signal

Development ◽  
1992 ◽  
Vol 114 (2) ◽  
pp. 317-330 ◽  
Author(s):  
O. Bossinger ◽  
E. Schierenberg
Keyword(s):  
Caenorhabditis Elegans ◽  
Low Cost ◽  
Free Living ◽  
Tissue Specific ◽  
C Elegans ◽  
Specific Accumulation ◽  
In Vivo Analysis

The pattern of autofluorescence in the two free-living namatodes Rhabditis dolichura and Caenorhabditis compared. In C. elegans, during later embryogenesis cells develop a typical bluish autofluorescence as illumination, while in Rh. dolichura a strong already present in the unfertilized egg. Using a new,

scholarly journals Edible Flowers of Tagetes erecta L. as Functional Ingredients: Phenolic Composition, Antioxidant and Protective Effects on Caenorhabditis elegans

Nutrients ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 2002 ◽  
Author(s):  
Cristina Moliner ◽  
Lillian Barros ◽  
Maria Dias ◽  
Víctor López ◽  
Elisa Langa ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
In Vivo Model ◽  
Tagetes Erecta ◽  
Protective Effects ◽  
Phenolic Composition ◽  
C Elegans ◽  
Amyloid Toxicity ◽  
Phenolic Profiles ◽  
Tagetes Erecta L

Tagetes erecta L. has long been consumed for culinary and medicinal purposes in different countries. The aim of this study was to explore the potential benefits from two cultivars of T. erecta related to its polyphenolic profile as well as antioxidant and anti-aging properties. The phenolic composition was analyzed by LC-DAD-ESI/MSn. Folin-Ciocalteu, DPPH·, and FRAP assays were performed in order to evaluate reducing antiradical properties. The neuroprotective potential was evaluated using the enzymes acetylcholinesterase and monoamine oxidase. Caenorhabditis elegans was used as an in vivo model to assess extract toxicity, antioxidant activity, delayed aging, and reduced β-amyloid toxicity. Both extracts showed similar phenolic profiles and bioactivities. The main polyphenols found were laricitin and its glycosides. No acute toxicity was detected for extracts in the C. elegans model. T. erecta flower extracts showed promising antioxidant and neuroprotective properties in the different tested models. Hence, these results may add some information supporting the possibilities of using these plants as functional foods and/or as nutraceutical ingredients.

scholarly journals Neural and genetic degeneracy underlies Caenorhabditis elegans feeding behavior

2014 ◽  
Vol 112 (4) ◽  
pp. 951-961 ◽  
Author(s):  
Nicholas F. Trojanowski ◽  
Olivia Padovan-Merhar ◽  
David M. Raizen ◽  
Christopher Fang-Yen
Keyword(s):  
Caenorhabditis Elegans ◽  
Neural Circuit ◽  
Dependent Manner ◽  
State Dependent ◽  
Excitatory Pathways ◽  
Genetic Mechanisms ◽  
Genetic Level ◽  
Pharyngeal Pumping ◽  
Robust Network

Degenerate networks, in which structurally distinct elements can perform the same function or yield the same output, are ubiquitous in biology. Degeneracy contributes to the robustness and adaptability of networks in varied environmental and evolutionary contexts. However, how degenerate neural networks regulate behavior in vivo is poorly understood, especially at the genetic level. Here, we identify degenerate neural and genetic mechanisms that underlie excitation of the pharynx (feeding organ) in the nematode Caenorhabditis elegans using cell-specific optogenetic excitation and inhibition. We show that the pharyngeal neurons MC, M2, M4, and I1 form multiple direct and indirect excitatory pathways in a robust network for control of pharyngeal pumping. I1 excites pumping via MC and M2 in a state-dependent manner. We identify nicotinic and muscarinic receptors through which the pharyngeal network regulates feeding rate. These results identify two different mechanisms by which degeneracy is manifest in a neural circuit in vivo.

scholarly journals Eukaryotic initiation factor EIF-3.G augments mRNA translation efficiency to regulate neuronal activity

2021 ◽  
Author(s):  
Stephen M Blazie ◽  
Seika Takayanagi-Kiya ◽  
Katherine A McCulloch ◽  
Yishi Jin
Keyword(s):  
Rna Binding ◽  
Mrna Translation ◽  
Initiation Factor ◽  
Translation Efficiency ◽  
Dependent Manner ◽  
Control Activity ◽  
C Elegans ◽  
Protein Levels ◽  
Neuronal Protein

AbstractThe translation initiation complex eIF3 imparts specialized functions to regulate protein expression. However, understanding of eIF3 activities in neurons remains limited despite widespread dysregulation of eIF3 subunits in neurological disorders. Here, we report a selective role of theC. elegansRNA-binding subunit EIF-3.G in shaping the neuronal protein landscape. We identify a missense mutation in the conserved Zinc-Finger (ZF) of EIF-3.G that acts in a gain-of-function manner to dampen neuronal hyperexcitation. Using neuron type-specific seCLIP, we systematically mapped EIF-3.G-mRNA interactions and identified EIF-3.G occupancy on GC-rich 5′UTRs of a select set of mRNAs enriched in activity-dependent functions. We demonstrate that the ZF mutation in EIF-3.G alters translation in a 5′UTR dependent manner. Our study reveals anin vivomechanism for eIF3 in governing neuronal protein levels to control activity states and offers insights into how eIF3 dysregulation contributes to neuronal disorders.

scholarly journals Identification of gmhA, a Yersinia pestis Gene Required for Flea Blockage, by Using a Caenorhabditis elegans Biofilm System

2005 ◽  
Vol 73 (11) ◽  
pp. 7236-7242 ◽  
Author(s):  
Creg Darby ◽  
Sandya L. Ananth ◽  
Li Tan ◽  
B. Joseph Hinnebusch
Keyword(s):  
Caenorhabditis Elegans ◽  
Yersinia Pestis ◽  
Biofilm Formation ◽  
Yersinia Pseudotuberculosis ◽  
C Elegans ◽  
Transposon Insertion ◽  
Insertion Mutants ◽  
Random Screening

ABSTRACT Yersinia pestis, the cause of bubonic plague, blocks feeding by its vector, the flea. Recent evidence indicates that blockage is mediated by an in vivo biofilm. Y. pestis and the closely related Yersinia pseudotuberculosis also make biofilms on the cuticle of the nematode Caenorhabditis elegans, which block this laboratory animal's feeding. Random screening of Y. pseudotuberculosis transposon insertion mutants with a C. elegans biofilm assay identified gmhA as a gene required for normal biofilms. gmhA encodes phosphoheptose isomerase, an enzyme required for synthesis of heptose, a conserved component of lipopolysaccharide and lipooligosaccharide. A Y. pestis gmhA mutant was constructed and was severely defective for C. elegans biofilm formation and for flea blockage but only moderately defective in an in vitro biofilm assay. These results validate use of the C. elegans biofilm system to identify genes and pathways involved in Y. pestis flea blockage.

scholarly journals In the Model Host Caenorhabditis elegans, Sphingosine-1-Phosphate-Mediated Signaling Increases Immunity toward Human Opportunistic Bacteria

2020 ◽  
Vol 21 (21) ◽  
pp. 7813
Author(s):  
Kiho Lee ◽  
Iliana Escobar ◽  
Yeeun Jang ◽  
Wooseong Kim ◽  
Frederick M. Ausubel ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Stress Responses ◽  
Mapk Signaling ◽  
Dependent Manner ◽  
Cellular Functions ◽  
Kinase Gene ◽  
Concentration Dependent Manner ◽  
C Elegans ◽  
Opportunistic Bacteria ◽  
Free Living Nematode

Sphingosine-1-phophate (S1P) is a sphingolipid-derived signaling molecule that controls diverse cellular functions including cell growth, homeostasis, and stress responses. In a variety of metazoans, cytosolic S1P is transported into the extracellular space where it activates S1P receptors in a concentration-dependent manner. In the free-living nematode Caenorhabditis elegans, the spin-2 gene, which encodes a S1P transporter, is activated during Gram-positive or Gram-negative bacterial infection of the intestine. However, the role during infection of spin-2 and three additional genes in the C. elegans genome encoding other putative S1P transporters has not been elucidated. Here, we report an evolutionally conserved function for S1P and a non-canonical role for S1P transporters in the C. elegans immune response to bacterial pathogens. We found that mutations in the sphingosine kinase gene (sphk-1) or in the S1P transporter genes spin-2 or spin-3 decreased nematode survival after infection with Pseudomonas aeruginosa or Enterococcus faecalis. In contrast to spin-2 and spin-3, mutating spin-1 leads to an increase in resistance to P. aeruginosa. Consistent with these results, when wild-type C. elegans were supplemented with extracellular S1P, we found an increase in their lifespan when challenged with P. aeruginosa and E. faecalis. In comparison, spin-2 and spin-3 mutations suppressed the ability of S1P to rescue the worms from pathogen-mediated killing, whereas the spin-1 mutation had no effect on the immune-enhancing activity of S1P. S1P demonstrated no antimicrobial activity toward P. aeruginosa and Escherichia coli and only minimal activity against E. faecalis MMH594 (40 µM). These data suggest that spin-2 and spin-3, on the one hand, and spin-1, on the other hand, transport S1P across cellular membranes in opposite directions. Finally, the immune modulatory effect of S1P was diminished in C. eleganssek-1 and pmk-1 mutants, suggesting that the immunomodulatory effects of S1P are mediated by the p38 MAPK signaling pathway.

scholarly journals Rosemary Flowers as Edible Plant Foods: Phenolic Composition and Antioxidant Properties in Caenorhabditis elegans

Antioxidants ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 811
Author(s):  
Cristina Moliner ◽  
Víctor López ◽  
Lillian Barros ◽  
Maria Inês Dias ◽  
Isabel C. F. R. Ferreira ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Antioxidant Properties ◽  
Ethanolic Extract ◽  
Food Ingredient ◽  
Edible Plant ◽  
Phenolic Profile ◽  
C Elegans ◽  
Rosmarinus Officinalis L

Rosmarinus officinalis L., commonly known as rosemary, has been largely studied for its wide use as food ingredient and medicinal plant; less attention has been given to its edible flowers, being necessary to evaluate their potential as functional foods or nutraceuticals. To achieve that, the phenolic profile of the ethanolic extract of R. officinalis flowers was determined using LC-DAD-ESI/MSn and then its antioxidant and anti-ageing potential was studied through in vitro and in vivo assays using Caenorhabditis elegans. The phenolic content was 14.3 ± 0.1 mg/g extract, trans rosmarinic acid being the predominant compound in the extract, which also exhibited a strong antioxidant capacity in vitro and increased the survival rate of C. elegans exposed to lethal oxidative stress. Moreover, R. officinalis flowers extended C. elegans lifespan up to 18%. Therefore, these findings support the potential use of R. officinalis flowers as ingredients to develop products with pharmaceutical and/or nutraceutical potential.

scholarly journals Piquiá Shells (Caryocar villosum): A Fruit by-Product with Antioxidant and Antiaging Properties in Caenorhabditis elegans

2020 ◽  
Vol 2020 ◽  
pp. 1-19 ◽  
Author(s):  
Mariana Roxo ◽  
Herbenya Peixoto ◽  
Pille Wetterauer ◽  
Emerson Lima ◽  
Michael Wink
Keyword(s):  
Caenorhabditis Elegans ◽  
Lethal Dose ◽  
Pcr Analysis ◽  
Transcriptional Level ◽  
Dependent Manner ◽  
Wild Type ◽  
Fluorescent Reporter ◽  
Triterpenoid Saponins ◽  
Promising Source

In a context of rising demand for sustainable antiaging interventions, fruit processing by-products are a promising source of bioactive compounds for the production of antiaging dietary supplements. Piquiá (Caryocar villosum) is a native Amazonian fruit consisting of 65% nonedible shells. In the present study, the phytochemical profile of a hydroalcoholic extract of piquiá shells (CV) was characterized by LC-MS/MS analysis. Its antioxidant and antiaging activities were investigated using the nematode Caenorhabditis elegans as an in vivo model. CV is mainly composed by hydrolysable tannins and triterpenoid saponins. The extract enhanced stress resistance of wild-type and mutant worms by reducing the intracellular levels of reactive oxygen species (ROS) and by increasing their survival against a lethal dose of the prooxidant juglone. These effects involved the upregulation of sod-3 and downregulation of gst-4 and hsp-16.2, studied through the GFP fluorescent reporter intensity and at the transcriptional level by qRT-PCR analysis. CV extended the lifespan of wild-type worms in a DAF-16/FoxO- and SKN-1/Nrf-dependent manner. Taken together, our findings indicate piquiá shells as potential candidates for nutraceutical applications. Further studies are needed to validate the relevance of our findings to antiaging interventions in humans.

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