Although the phenotypes of the human diseases and the mutant defects in C. elegans seem about as unrelated as possible, the cellular and molecular details of many of these defects are highly related. Using C. elegans as a model organism, much can be learned at the cellular and molecular level about a specific biological process, by understanding the mode of action of the orthologous genes involved.
We can provide preclinical assessments of disease pathology and phenotype progression in the genetic or compound context of your choice.
- Determine gene variant effects on disease pathological state
- Determine drug, compound, or toxin effects on disease pathological state
Assays Used for Disease Modeling
Quantify the activity of a worm population.
Quantify detailed movement measures from individual worms.
Quantify expression levels of a gene of interest.
Get survival curves for a cohort of worms.
Measure the vitality of worms as they age.
Growth Rate Analysis
Quantify the size of worms as they age.
The data below are generated using a variety of assays.
Figure 1. Pharyngeal Pumping Gross Movement Analysis. Worm population liquid movement analysis comparison between wild-type Bristol N2 worms, STXBP1 ortholog unc-18 KO and hSTXBP1 gene insertion (“gene swap”) lines; data obtained using the WMicroTracker instrument.
*See NemaMetrix wMicroTracker for additional experiment information.
Figure 2. Pharyngeal Pumping Fine Movement Analysis. Pharyngeal pumping frequency in wild-type Bristol N2 worms as compared with the STXBP1 ortholog unc-18 KO and hSTXBP1 gene insertion (“gene swap”); data obtained using the ScreenChip system.
*EPG – electropharyngeogram (pumping activity trace)
**See NemaMetrix ScreenChip System for additional experiment information.
Figure 3. Pharyngeal Pumping Fine Movement Analysis. Comparison of pharyngeal pumping frequency in wild-type Bristol N2 worms treated with control or rabies-derived peptide toxin.
*adapted from Hueffer et al, 2017.
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Applications of the C. elegans Model in Disease Modeling
Nematodes are integral to the discovery of genetic determinants of disease pathology.
- C. elegans used successfully as a tool for identifying neuroprotective genes and pathways.48
- Nematodes used for modeling tauopathies, repeat-associated diseases, muscular dystrophy disorders, and other neuromuscular pathologies.7
- C. elegans used as a comprehensive model for identifying variant gene toxicity and pathological mechanism.49
Combine the strength of a whole-organism approach with the detail of thorough molecular understanding.51
- Exploit the power of model system genetic manipulation with the power of population-scale statistics.52
- Synaptic connectivity in the worm has been fully mapped and determined via serial section electron microscopy.51
- The worm provides an “array of classical neurotransmitters which approaches the complexity of vertebrate nervous systems.” 60
- Toxicity studies in C. elegans are reported to be as predictive as mouse LD50 rankings.50
Nematodes are invaluable for the discovery therapeutic compounds targeting high-impact diseases.45
- C. elegans is a powerful tool for compound screening due to highly conserved and well-characterized neurological pathways.
- C. elegans used as a comprehensive model for identifying various compound classes that influencing progression of disease pathology.46
- Nematode model used for Screening/Target Identification, Target Validation, Mechanism of Action (MOA), and Toxicity Assessment studies.47
C. elegans as a research tool for disease modeling:
Published Research and Outcomes
Disease modeling in genetic space: published approaches and outcomes of C. elegans studies.
Single-Gene Manipulations and Classical Genetics
- Determination that genes influencing lifespan delay onset of pathogenic phenotypes of Parkinson’s Disease (PD).36
- Development of a C. elegans neuromuscular-based model for Autism Spectrum Disorder (ASD).12
- Discovery of evolutionarily conserved proteins playing cooperative functions in Spinal Muscular Atrophy (SMA) pathogenesis.39
Genome-Wide Association (GWA) Studies
- Discovery of NCLAD, a negative regulator of endocytosis, in ameliorating SMA-associated pathological defects.23
- Discovery of twelve genes modulating SMN loss-of-function defects in SMA pathology.42
- Identification of nuclear envelope components contributing to Emery-Dreifuss Muscular Dystrophy.43
Disease modeling in a compound context: published approaches and outcomes of C. elegans studies.
- Discovery of >10 flavonoid analogs imparting neuronal function protection in a Huntington’s Disease (HD) model.15
- Determination that sex-hormones and Hormone Replacement Therapy (HRT) impart a neuroprotective effect against Alzheimer’s Disease (AD).37
- Characterization of the squalamine-related compound trodusquemine in inhibition of aggregation pathways in Parkinson’s Disease (PD).37
- Description of guarana as a neuroprotective agent during Parkinson’s (PD), Alzheimer’s (AD), and Huntington’s Disease (HD) progression.41
Chemical Library Screens
- Determination of six chemical compounds ameliorating Spinal Muscular Atrophy (SMA) phenotypic dysfunction, from a library of >1000.44
- Description of tambulin treatment in curtailing and alleviating Parkinson’s Disease (PD) manifestations.40
- Tissenbaum, HA. Using C. elegans for aging research. Invertebr Reprod Dev. 2014 Jan 30; 59(sup1):59-63.
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- Sutphin GL, Korstanje R. 2016. Chapter 1: Longevity as a Complex Genetic Trait. In: Handbook of the Biology of Aging, 8th Ed. Kaeberlein MR, Martin GM, eds. San Diego, CA: Elsevier Academic Press, pp. 3-54.
- Sutphin GL, et al. Caenorhabditis elegans orthologs of human genes differentially expressed with age are enriched for determinants of longevity. Aging Cell. 2017 Aug; 16(4):672-682.
- Yanos ME, et al. Genome-wide RNAi longevity screens in Caenorhabditis elegans. Curr. Genomics. 2012; 13:508–518.
- Henderson ST, Rea SL, Johnson TE. 2006. Chapter 13: Dissecting the Processes of Aging Using the Nematode Caenorhabditis elegans. In: Handbook of the Biology of Aging, 6th Ed. Masoro E, Austad S, eds. Burlington, MA: Elsevier Academic Press, pp. 360-399.
- Sin O, Michels H, Nollen EA. Genetic screens in Caenorhabditis elegans models for neurodegenerative diseases. Biochim Biophys Acta. 2014 Oct; 1842(10):1951-1959.
- Sinha A, Rae R. Genome-Wide RNAi Screens in C. elegans to Identify Genes Influencing Lifespan and Innate Immunity. Methods Mol Biol. 2016; 1470:171-82.
- Wang MC, Oakley HD, Carr CE, Sowa JN, Ruvkun G. Gene pathways that delay Caenorhabditis elegans reproductive senescence. PLoS Genet. 2014 Dec 4; 10(12):e1004752.
- Gao AW, de Bosa J, Sterkenb MG, Kammenga JE, Smith RL, Houtkooper RH. Forward and reverse genetics approaches to uncover metabolic aging pathways in Caenorhabditis elegans. Biochimica et Biophysica Acta. 2018 Sep; 1864(9):2697-2706.
- Gruber J, Ng LF, Poovathingal SK, Halliwell B. Deceptively simple but simply deceptive – Caenorhabditis elegans lifespan studies: Considerations for aging and antioxidant effects. FEBS Letters. 2009 Nov; 583(21):3377-3387.
- Schmeisser K, Fardghassemi Y, Parker JA. A rapid chemical-genetic screen utilizing impaired movement phenotypes in C. elegans: Input into genetics of neurodevelopmental disorders. Experimental Neurology. 2017 Jul; 293:101-114. **wMicroTracker USED**
- Sinha A, Rae R. A functional genomic screen for evolutionarily conserved genes required for lifespan and immunity in germline-deficient C. elegans. PLoS One. 2014 Aug 5; 9(8):e101970.
- Bansal A, Kwon ES, Conte D Jr, Liu H, Gilchrist MJ, MacNeil LT, Tissenbaum HA. Transcriptional regulation of Caenorhabditis elegans FOXO/DAF-16 modulates lifespan. Longev Healthspan. 2014 Apr 23;3:5.
- Farina F, et al. The stress response factor daf-16/FOXO is required for multiple compound families to prolong the function of neurons with Huntington’s disease. Sci Rep. 2017 Jun 21; 7(1):4014.
- Hotzi B, et al. Sex-specific regulation of aging in Caenorhabditis elegans. Aging Cell. 2018 Jun; 17(3):e12724.
- Huang CH, et al. Analysis of lifespan-promoting effect of garlic extract by an integrated metabolo-proteomics approach. J Nutr Biochem. 2015 Aug; 26(8):808-17.
- Artal-Sanz M, de Jong L, Tavernarakis N. Caenorhabditis elegans: A versatile platform for drug discovery. Biotechnol. J. 2006; 1:1405–1418.
- Kennedy B, Pennypacker JK. Aging interventions get human. Oncotarget. 2015 Jan; 6(2): 590–591.
- Coutts F, Palmos AB, Duarte RRR, de Jong S, Lewis CM, Dima D, Powell TR. The polygenic nature of telomere length and the anti-ageing properties of lithium. Neuropsychopharmacology. 2019; 44: 757–765.
- Keane M, de Magalhaes JP. MYCN/LIN28B/Let-7/HMGA2 pathway implicated by meta-analysis of GWAS in suppression of post-natal proliferation thereby potentially contributing to aging. Mech Ageing Dev. 2013 Jul-Aug; 134(7-8): 346-348.
- Iakoubov L, Mossakowska M, Szwed M, Duan Z, Sesti F, Puzianowska-Kuznicka M. A Common Copy Number Variation (CNV) Polymorphism in the CNTNAP4 Gene: Association with Aging in Females. PLoS One. 2013; 8(11): e79790.
- Riessland M, et al. Neurocalcin Delta Suppression Protects against Spinal Muscular Atrophy in Humans and across Species by Restoring Impaired Endocytosis. Am J Hum Genet. 2017 Feb 2; 100(2): 297-315.
- Cook DE, et al. The Genetic Basis of Natural Variation in Caenorhabditis elegans Telomere Length. Genetics. 2016 Sep; 204(1): 371–383.
- Brunquell J, Morris S, Lu Y, Cheng F, Westerheide SD.The genome-wide role of HSF-1 in the regulation of gene expression in Caenorhabditis elegans. BMC Genomics. 2016 Aug 5; 17: 559.
- Rangaraju S, Levey DF, Nho K, Jain N, Andrews KD, Le-Niculescu H, Salomon DR, Saykin AJ, Petrascheck M, Niculescu AB. Mood, stress and longevity: convergence on ANK3. Molecular Psychiatry. 2016; (21): 1037–1049.
- Melov S, et al. Extension of life-span with superoxide dismutase/catalase mimetics. Science. 2000 Sep 1;289(5484):1567-9.
- Alavez S, Vantipalli MC, Zucker DJ, Klang IM, Lithgow GJ. Amyloid-binding compounds maintain protein homeostasis during ageing and extend lifespan. Nature. 2011 Apr 14; 472(7342): 226-9.
- Lucanic M, Held JM, Vantipalli MC, Klang MI, Grahan JB, Gibson, BW, Lithgow GJ, Gill MS. N-acylethanolamine signaling mediates the effect of diet on lifespan in C. elegans. Nature. 2011 May 12; 473(7346): 226–229.
- Samuelson AV, Klimczak RR, Thompson DB, Carr CE, Ruvkun G. Identification of Caenorhabditis elegans genes regulating longevity using enhanced RNAi-sensitive strains. Cold Spring Harb Symp Quant Biol. 2007; 72: 489-97.
- Hamilton B, Don Y, Shindo M, Liu Q, Odell I, Ruvkin G, Lee SS. A systematic RNAi screen for longevity genes in C. elegans. Genes Dev. 2005 Jul 1; 19(13): 1544-55.
- Hansen M, Hsu AL, Dillin A, Kenyon C. New genes tied to endocrine, metabolic, and dietary regulation of lifespan from a Caenorhabditis elegans genomic RNAi screen. PLoS Genet. 2005 Jul; 1(1): 119-28.
- Lee SS, Lee RY, Fraser AG, Kamath RS, Ahringer J, Ruvkun G. A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity. Nat Genet. 2003 Jan; 33(1): 40-8.
- Chen AL, et al. Pharmacological convergence reveals a lipid pathway that regulates C. elegans lifespan. Nat Chem Biol. 2019 May; 15(5): 453-462.
- García-Casas P, Arias-Del-Val J, Alvarez-Illera P, Wojnicz A, de Los Ríos C, Fonteriz RI, Montero M, Alvarez J. The Neuroprotector Benzothiazepine CGP37157 Extends Lifespan in C. elegans Worms. Front Aging Neurosci. 2019 Jan 17; 10: 440.
- Cooper JF, Dues DJ, Spielbauer KK, Machiela E, Senchuk MM, Van Raamsdonk JM. Delaying aging is neuroprotective in Parkinson’s disease: a genetic analysis in C. elegans models. NPJ Parkinsons Dis. 2015; 1: 15022.
- Zárate S, Stevnsner T, Gredilla R. Role of Estrogen and Other Sex Hormones in Brain Aging, Neuroprotection and DNA Repair. Front Aging Neurosci. 2017; 9: 430.
- Perni M, et al. Multistep Inhibition of α-Synuclein Aggregation and Toxicity in Vitro and in Vivo by Trodusquemine. ACS Chem Biol. 2018 Aug 17; 13(8): 2308-2319.
- Di Giorgio ML, et al. WDR79/TCAB1 plays a conserved role in the control of locomotion and ameliorates phenotypic defects in SMA models. Neurobiol Dis. 2017 Sep; 105: 42-50.
- Pandey T, Sammi SR, Nooreen Z, Mishra A, Ahmad A, Bhatta RS, Pandey R. Anti-ageing and anti-Parkinsonian effects of natural flavonol, tambulin from Zanthoxyllum aramatum promotes longevity in Caenorhabditis elegans. Exp Gerontol. 2019 Jun; 120: 50-61.
- Boasquívis PF, Silva GMM, Paiva FA, Cavalcanti RM, Nunez CV, de Paula Oliveira R. Guarana (Paullinia cupana) Extract Protects Caenorhabditis elegans Models for Alzheimer Disease and Huntington Disease through Activation of Antioxidant and Protein Degradation Pathways. Oxid Med Cell Longev. 2018 Jul 4; 2018: 9241308.
- Dimitriadi M, et al. Conserved genes act as modifiers of invertebrate SMN loss of function defects. PLoS Genet. 2010 Oct 28; 6(10): e1001172.
- González-Aguilera C, Ikegami K, Ayuso C, de Luis A, Íñiguez M, Cabello J, Lieb JD, Askjaer P. Genome-wide analysis links emerin to neuromuscular junction activity in Caenorhabditis elegans. Genome Biol. 2014 Feb 3; 15(2): R21.
- Sleigh JN, Buckingham SD, Esmaeili B, Viswanathan M, Cuppen E, Westlund BM, Sattelle DB. A novel Caenorhabditis elegans allele, smn-1(cb131), mimicking a mild form of spinal muscular atrophy, provides a convenient drug screening platform highlighting new and pre-approved compounds. Hum Mol Genet. 2011 Jan 15; 20(2): 245-60.
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