Disease and Drugs

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C. elegans as a model system to study disease and disease genes

Major areas where elegans disease modeling exists

1. Neuromuscular diseases:

Amyotrophic Lateral Sclerosis, Duchenne Muscular Dystrophy, Friedreich’s Ataxia, Inclusion Body Myositis, Spinal Muscular Atrophy (Human genes-SOD1, TDP43, DMD, FXN, APP, SMN; elegans counterparts: sod-1, tdp-1, dys-1, frh-1, apl-1, smn-1)

2. Complex neurological diseases:

Parkinson’s, Alzheimer’s, Autism Spectrum disorder: modeling via transgenic expression of human genes. Parkinson’s disease: modeling via transgenic expression of human genes alpha-synuclein (PARK1); other genes involved: leucine-rich repeat kinase 2 (LRRK2, also known as PARK8); ubiquitin E3 ligase (PARK2); kinase PINK1 (PARK6); oncogene DJ-1 (PARK7); Elegans model also used to study neurotoxic and neuroprotective compounds. Alzheimer’s disease and Tauopathies: Human genes APP, PSEN1, PSEN2 and MAPT gene encoding tau; elegans apl-1, elegans presenilins-sel-12, hop-1, spe-4 ; elegans effectors of transgenic expression of tau: sut-1, sut-2. Autism spectrum disorders: Human Shank family proteins, neuroligins, neurexins; Elegans: shn-1, nlg-1, nrx-1.

3. Ciliary diseases:

Cystic kidney dieases: Polycystic kidney disease (PKD), human genes -PKD1, PKD2. Elegans: lov-1, pkd-2; Autosomal recessive polycystic kidney disease-genes Tg737orpk, hetrotrimeric kinesin-II, KIF3A, KIF17 Elegans: osm-5, klp-11, klp-20, kap-1, osm-3; Bardet-Biedl syndrome, human genes-BBS genes, elegans: bbs genes; Nephronophthisis, human genes-NPHP1, NPHP2, NPHP3, NPHP4 elegans genes: M28.7, T28D6.4, klc-1, klc-2, R13H4.1.

4. Laminopathic diseases:

Mutations in lamin (LMNA) cause: Emery-Dreifuss muscular dystrophy (EDMD), gene-Emerin, elegans-emr-1 LMNA-related congenital muscular dystrophy (L-CMD) Limb-girdle muscular dystrophy and dilated cardiomyopathy Neuropathic Charcot-Marie-Tooth disorder Lipodystrophies: Mandicyloacral dysplasia, Dunnigan-type familial partial lipodystrophy Systemic premature aging syndromes: Hutchison-Gilford progeria, Werner syndrome

5. Intestinal inflammatory diseases:

Human gene: Toll-like Receptor 4 (TLR4) Ulcerative colitis Crohn’s disease Necrotizing enterocolitis (NEC)

6. Obesity

7. Prion diseases

Human disease relevance descriptions

Human disease relevance descriptions were introduced in late 2011, on the WormBase gene page, to serve both the worm researcher and the biomedical researcher from outside the worm community. This description alerts researchers to the fact that the worm is either an effective model system or is being developed as a model system to study the disease/gene. For under-studyed genes in elegans for which there are only sequence names, human ortholog and disease information provide clues to the function of the gene.

Human disease relevance descriptions are written in most cases, to include:

  • Orthology to the human disease gene or family of genes, may include domain information.
  • The different types of human diseases known to have mutations in the human gene ortholog. OMIM accession numbers are provided below the description which are links into the OMIM resource.
  • Functional similarities or differences between the human/vertebrate and worm gene.
  • Data from worm studies that add new knowledge, or validate existing knowledge from studies in other species or experimental systems (eg., cell culture, etc.).
  • For understudyed genes in elegans for which there are only sequence names, human ortholog and disease information provide insights into elegans gene function
  • Also serves the purpose of making automated descriptions more information-rich and useful to users:

Examples of automated descriptions based on OMIM orthology that existed in WormBase prior to 2012:

1. T27A3.6 is orthologous to the human gene MOLYBDENUM COFACTOR BIOSYSTHESIS PROTEIN E (MOCS2; OMIM:603708), which when mutated leads to disease.

2. Y24D9A.8 is orthologous to the human gene TRANSALDOLASE 1 (TALDO1; OMIM:602063), which when mutated leads to disease.

3. Y110A7A.9 is orthologous to the human gene KIAA1351 PROTEIN (WDR11; OMIM:606417), which when mutated leads to disease.

For WormBase Progress Report (written May/June 2012)

In recent years, C. elegans has been widely used as a system to study human disease gene orthologs and to model human disease and drug-disease interactions. In early 2012, we began writing ‘Human Disease Relevance’ descriptions, as an addition to the gene pages, keeping in mind the non-worm biomedical community. These descriptions combine information obtained from automated ortholog identification methods which are mostly based on sequence, with curated information about disease modeling, from the published worm literature. These descriptions include the following information: (1) Orthology to the human disease gene or family of genes and domain information (2) Diseases associated with mutations in the human gene, with OMIM accessions which are links into the OMIM resource (Online Mendelian Inheritance in Man; http://www.ncbi.nlm.nih.gov/omim) (3) New information or validations that studies in C. elegans have yielded to the study of disease gene/disease. Currently, we have 80 of these descriptions in the database. --End report--

C. elegans as a model to study infectious agents

Bacteria and Biofilms
Parasitic nematodes
Fungal pathogens
  • human fungal pathogen Cryptococcus neoformans

Textpresso keyword search 'Cryptococcus neoformans' returns 117 documents

C. elegans as a model to study metal toxicity and detoxification

Using C. elegans to study the effects of space flight

C. elegans as a model system to study drugs

C. elegans is being used to study:

  • metal toxicity and detoxification
  • the effects of a drug/chemical on disease phenotypes
  • identify gene targets for a given drug/chemical
  • mode of action of a drug/chemical (MOA)

Types of drugs being studied include:

  • Antifungal agents
  • Antimicrobial agents
  • Antiparasitic drugs--Aldicarb, Ivermectin, Levamisole
  • Anti-depressants--Fluoxetine, Imipramine
  • Anaesthic--Halothane
  • Anticancer drugs--Farnesyltransferase inhibitors (FTIs)
  • Anticonvulsants--Ethosuximide, Arimethadione
  • Alkaloid drugs--Nicotine
  • Immunosuppressants--Prednisone
  • Nutritional supplements--Resveratrol, Gingko biloba
  • Opioid toxins--MPTP/MPP+
  • Pychoactive drug--Ethanol

Textpresso-based systems to flag papers

Pipeline for identifying papers with disease or disease gene ortholog

Pipeline for identifying papers with drugs

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