Caenorhabditis elegans as a Model System for Triplet Repeat Diseases

  • Cindy Voisine
  • Anne C. Hart
Part of the Methods in Molecular Biology™ book series (MIMB, volume 277)


Common features underlie the generation and function of neurons in multicellular animals. It is likely that conserved pathways and genes also are involved in neuronal degeneration and malfunction. To address the molecular mechanisms of complex human neurological disorders, many investigators are choosing to study these diseases in simpler organisms. The nematode Caenorhabditis elegans provides an excellent model system to address genetically the mechanisms of triplet repeat diseases. Advantages of using C. elegans as a model system include the ease of genetic manipulation, the sequenced genome, and a short life cycle. Furthermore, researchers can precisely identify specific neurons and follow their development or survival throughout the animal’s lifetime. This chapter describes the tools and approaches for modeling triplet repeat diseases in C. elegans with a specific emphasis on polyglutamine (polyQ) diseases. Although the bulk of the chapter is devoted to generating a polyQ disease model in C. elegans, it also addresses potential avenues for assessing the impact of specific candidate genes/pathways on the disease process, including cell death and aging.

Key Words

Caenorhabditis elegans neurodegeneration triplet repeat diseases polyglutamine diseases Huntington’s disease 


  1. 1.
    Zoghbi, H. Y. and Orr, H. T. (2000) Glutamine repeats and neurodegeneration. Annu. Rev. Neurosci. 23, 217–247.PubMedCrossRefGoogle Scholar
  2. 2.
    Ross, C. A. (2000) PolyQ pathogenesis: emergence of unifying mechanisms for Huntington’s disease and related disorders. Neuron 35(5), 819–822.CrossRefGoogle Scholar
  3. 3.
    Orr, H. T. (2001) Beyond the Qs in the polyQ diseases. Genes Dev. 15, 925–932.PubMedCrossRefGoogle Scholar
  4. 4.
    Tobin, A. J. and Signer, E. R. (2000) Huntington’s disease: the challenge for cell biologists. Trends Cell Biol. 10(12), 531–536.PubMedCrossRefGoogle Scholar
  5. 5.
    Campuzano, V., Montermini, L., Molto, M. D., et al. (1996) Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 271(5254), 1423–1427.PubMedCrossRefGoogle Scholar
  6. 6.
    Campuzano, V., Montermini, L., Lutz, Y., et al. (1997) Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes. Hum. Mol. Genet. 6(11), 1771–1780.PubMedCrossRefGoogle Scholar
  7. 7.
    Satyal, S. H., Schmidt, E., Kitagawa, K., et al. (2000) PolyQ aggregates alter protein folding homeostasis in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 97(11), 5750–5755.CrossRefGoogle Scholar
  8. 8.
    Parker, J. A., Connolly, J. B., Wellington, C., et al. (2001) Expanded polyQs in Caenorhabditis elegans cause axonal abnormalities and severe dysfunction of PLM mechanosensory neurons without cell death. Proc. Natl. Acad. Sci. USA 98(23), 13,318–13,323.PubMedCrossRefGoogle Scholar
  9. 9.
    Faber, P. W., Alter, J. R., MacDonald, M. E., et al. (1999) PolyQ-mediated dysfunction and apoptotic death of a Caenorhabditis elegans sensory neuron. Proc. Natl. Acad. Sci. USA 96(1), 179–184.PubMedCrossRefGoogle Scholar
  10. 10.
    DiFiglia, M., Sapp, E., Chase, K. O., et al. (1997) Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277(5334), 1990–1993.PubMedCrossRefGoogle Scholar
  11. 11.
    Vonsattel, J. P., Meyers, R. H., Stevens T. J., et al. (1985) Neuropathological classification of Huntington’s disease. J. Neuropathol. Exp. Neurol. 44(6), 559–577.PubMedCrossRefGoogle Scholar
  12. 12.
    Zoghbi, H. Y. and Orr, H. T. (1995) Spinocerebellar ataxia type 1. Semin. Cell Biol. 6(1), 29–35.PubMedCrossRefGoogle Scholar
  13. 13.
    White, J. G., Southgate, E., Thompson, J. N., et al. (1976) The structure of the nervous system of the nematode Caenorhabditis elegans. Phil. Trans. R. Soc. (Lond.) B(314), 1–340.Google Scholar
  14. 14.
    Fukushige, T., Hawkins, M. G., and McGhee, J. D. (1998) The GATA-factor elt-2 is essential for formation of the Caenorhabditis elegans intestine. Dev. Biol. 198(2), 286–302.PubMedGoogle Scholar
  15. 15.
    Labouesse, M., Hartwieg, E., and Horvitz, H. R. (1996) The Caenorhabditis elegans LIN-26 protein is required to specify and/or maintain all non-neuronal ectodermal cell fates. Development 122(9), 2579–2588.PubMedGoogle Scholar
  16. 16.
    Gaudet, J. and Mango, S. E. (2002) Regulation of organogenesis by the Caenorhabditis elegans FoxA protein PHA-4. Science 295(5556), 821–825.PubMedCrossRefGoogle Scholar
  17. 17.
    Davis, M. W., Somerville, D., Lee, R. Y., et al. (1995) Mutations in the Caenorhabditis elegans Na,K-ATPase alpha-subunit gene, eat-6, disrupt excitable cell function. J. Neurosci. 15(12), 8408–8418.PubMedGoogle Scholar
  18. 18.
    Miller, D. M., 3rd, Olson, J. S., Pflugrath, J. W., et al. (1983) Differential localization of two myosins within nematode thick filaments. Cell 34(2), 477–490.PubMedCrossRefGoogle Scholar
  19. 19.
    Chalfie, M., Sulston, J. E., White, J. G., et al. (1985) The neural circuit for touch sensitivity in Caenorhabditis elegans. J. Neurosci. 5(4), 956–964.PubMedGoogle Scholar
  20. 20.
    Maduro, M. and Pilgrim, D. (1995) Identification and cloning of unc-119, a gene expressed in the Caenorhabditis elegans nervous system. Genetics 141(3), 977–988.PubMedGoogle Scholar
  21. 21.
    McIntire, S. L., Jorgensen, E., and Horvitz, H. R. (1993) Genes required for GABA function in Caenorhabditis elegans. Nature 364(6435), 334–337.PubMedCrossRefGoogle Scholar
  22. 22.
    Hart, A. C., Sims, S., and Kaplan, J. M. (1995) Synaptic code for sensory modalities revealed by C. elegans GLR-1 glutamate receptor. Nature 378(6552), 82–85.PubMedCrossRefGoogle Scholar
  23. 23.
    Hart, A. C., Kass, J., Shapiro, J. E., et al. (1999) Distinct signaling pathways mediate touch and osmosensory responses in a polymodal sensory neuron. J. Neurosci. 19, 1952–1958.PubMedGoogle Scholar
  24. 24.
    Bargmann, C. (1993) Odorant selective genes and neurons mediate olfaction in C. elegans. Cell 74, 515–527.PubMedCrossRefGoogle Scholar
  25. 25.
    Kaplan, J. M. and Horvitz, H.R. (1993) A dual mechanosensory and chemosensory neuron in C. elegans. Proc. Natl. Acad. Sci. USA 90, 2227–2231.PubMedCrossRefGoogle Scholar
  26. 26.
    Troemel, E. R., Chou, J. H., Dwyer, N. D., et al. Divergent seven transmembrane receptors are candidate chemosensory receptors in C. elegans. Cell 83, 207–218.Google Scholar
  27. 27.
    Way, J. C. and Chalfie, M. (1989) The mec-3 gene of Caenorhabditis elegans requires its own product for maintained expression and is expressed in three neuronal cell types. Genes Dev. 3(12A), 1823–1833.PubMedCrossRefGoogle Scholar
  28. 28.
    Chalfie, M. and Sulston, J. (1981) Developmental genetics of the mechanosensory neurons of Caenorhabditis elegans. Dev. Biol. 82(2), 358–370.PubMedCrossRefGoogle Scholar
  29. 29.
    Loer, C. M. and Kenyon, C. J. (1993) Serotonin-deficient mutants and male mating behavior in the nematode Caenorhabditis elegans. J. Neurosci. 13(12), 5407–5417.PubMedGoogle Scholar
  30. 30.
    Desai, C., Garriga, G., McIntire, S. L., et al. (1988) A genetic pathway for the development of the Caenorhabditis elegans HSN motor neurons. Nature 336(6200), 638–646.PubMedCrossRefGoogle Scholar
  31. 31.
    Trent, C., Tsuing, N., and Horvitz, H. R. (1983) Egg-laying defective mutants of the nematode Caenorhabditis elegans. Genetics 104(4), 619–647.PubMedGoogle Scholar
  32. 32.
    Segalat, L., Elkes, D. A., and Kaplan, J. M. (1995) Modulation of serotonin-controlled behaviors by Go in Caenorhabditis elegans. Science 267(5204), 1648–1651.PubMedCrossRefGoogle Scholar
  33. 33.
    Sakahira, H., Breuer, P., Hayer-Hartl, M. K., et al. (2002) Molecular chaperones as modulators of polyQ protein aggregation and toxicity. Proc. Natl. Acad. Sci. USA 99(Suppl. 4), 16,412–16,418.PubMedCrossRefGoogle Scholar
  34. 34.
    Fernandez-Funez, P., Nino-Rosales, M. L., de Gouyon, B., et al. (2000) Identification of genes that modify ataxin-1-induced neurodegeneration. Nature 408, 101–106.PubMedCrossRefGoogle Scholar
  35. 35.
    Perkins, L. A., Hedgecock, E. M., Thomson, J. N., et al. (1986) Mutant sensory cilia in the nematode Caenorhabditis elegans. Dev. Biol. 117, 456–487.PubMedCrossRefGoogle Scholar
  36. 36.
    Liu, Q. A. and Hengartner, M. O. (1999) The molecular mechanism of programmed cell death in C. elegans. Ann. NY Acad. Sci. 887, 92–104.PubMedCrossRefGoogle Scholar
  37. 37.
    Hickey, M. A. and Chesselet, M. F. (2003) Apoptosis in Huntington’s disease. Prog. Neuropsychopharmacol. Biol. Psychiatry 27, 255–265.PubMedCrossRefGoogle Scholar
  38. 38.
    Chung, S., Gurniuenny, T. L., Hengartner, M. O., et al. (2000) A common set of engulfment genes mediates removal of both apoptotic and necrotic cell corpses in C. elegans. Nature Cell Biol. 2, 931–937.PubMedCrossRefGoogle Scholar
  39. 39.
    Xu, K., Tavernarakis, N., and Driscoll, M. (2001) Necrotic cell death in C. elegans requires the function of calreticulin and regulators of Ca(2+) release from the endoplasmic reticulum. Neuron 31, 957–971.PubMedCrossRefGoogle Scholar
  40. 40.
    Hekimi, S. and Guarente, L. (2003) Genetics and the specificity of the aging process. Science 299(5611), 1351–1354.PubMedCrossRefGoogle Scholar
  41. 41.
    Tatar, M., Bartke, A., and Antebi, A. (2003) The endocrine regulation of aging by insulinlike signals. Science 299(5611), 1346–1351.PubMedCrossRefGoogle Scholar
  42. 42.
    Tabrizi, S. J., Cleeter, M. W., Xuereb, J., et al. (1999) Biochemical abnormalities and excitotoxicity in Huntington’s disease brain. Ann. Neurol. 45(1), 25–32.PubMedCrossRefGoogle Scholar
  43. 43.
    Brouillet, E. and Hantraye, P. (1995) Effects of chronic MPTP and 3-nitropropionic acid in nonhuman primates. Curr. Opin. Neurol. 8(6), 469–473.PubMedCrossRefGoogle Scholar
  44. 44.
    Beal, M. F., Brouillet, E., Jenkins, B. G., et al. (1993) Neurochemical and histologic characterization of striatal excitotoxic lesions produced by the mitochondrial toxin 3-nitropropionic acid. J. Neurosci. 13(10), 4181–4192.PubMedGoogle Scholar
  45. 45.
    Bargmann, C. I. (1998) Neurobiology of the Caenorhabditis elegans genome. Science 282(5396), 2028–2033.PubMedCrossRefGoogle Scholar
  46. 46.
    Davis, M. W., Fleischhauer, R., Dent, J. A., et al. (1999) A mutation in the C. elegans EXP-2 potassium channel that alters feeding behavior. Science 286(5449), 2501–2504.PubMedCrossRefGoogle Scholar
  47. 47.
    Thomas, J. H. (1990) Genetic analysis of defecation in Caenorhabditis elegans. Genetics 124(4), 855–872.PubMedGoogle Scholar
  48. 48.
    Garcia-Anoveros, J., Ma, C., and Chalfie, M. (1995) Regulation of Caenorhabditis elegans degenerin proteins by a putative extracellular domain. Curr. Biol. 5(4), 441–448.PubMedCrossRefGoogle Scholar
  49. 49.
    Fire, A., Xu, S., Montgomery, M. K., et al. (1998) Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391(6669), 806–811.PubMedCrossRefGoogle Scholar
  50. 50.
    Timmons, L. and Fire, A. (1998) Specific interference by ingested dsRNA. Nature 395(6705), 854.PubMedCrossRefGoogle Scholar
  51. 51.
    Tabara, H., Grishok, A., and Mello, C. C. (1998) RNAi in C. elegans: soaking in the genome sequence. Science 282(5388), 430–431.PubMedCrossRefGoogle Scholar
  52. 52.
    Tavernarakis, N., Wang, S. L., Dorovkov, M., et al. (2000) Heritable and inducible genetic interference by double-stranded RNA encoded by transgenes. Nature Genet. 24(2), 180–183.PubMedCrossRefGoogle Scholar
  53. 53.
    Simmer, F., Tijsterman, M., Parrish, S., et al. (2002) Loss of the putative RNA-directed RNA polymerase RRF-3 makes C. elegans hypersensitive to RNAi. Curr. Biol. 12(15), 1317–1319.PubMedCrossRefGoogle Scholar
  54. 54.
    Brenner, S. (1974) The genetics of Caenorhabditis elegans. Genetics 77(1), 71–94.PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2004

Authors and Affiliations

  • Cindy Voisine
    • 1
  • Anne C. Hart
    • 1
  1. 1.Department of Pathology, Harvard Medical School, and Cancer CenterMassachusetts General Hospital EastCharlestown

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