What Can We Learn About Human Disease from the Nematode C. elegans?

Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1706)

Abstract

Numerous approaches have been taken in the hunt for human disease genes. The identification of such genes not only provides a great deal of information about the mechanism of disease development, but also provides potential avenues for better diagnosis and treatment. In this chapter, we review the use of the nonmammalian model organism C. elegans for the identification of human disease genes. Studies utilizing this relatively simple organism offer a good balance between the ability to recapitulate many aspects of human disease, while still offering an abundance of powerful cell biological, genetic, and genomic tools for disease gene discovery. C. elegans and other nonmammalian models have produced, and will continue to produce, key insights into human disease pathogenesis.

Key words

Caenorhabditis elegans Genetic screens Genomic screens RNAi GFP 

Notes

Acknowledgments

This work was supported by National Institutes of Health Grant 1R01ES025161 to S.A.

References

  1. 1.
    Aitman TJ, Boone C, Churchill GA, Hengartner MO, Mackay TF, Stemple DL (2011) The future of model organisms in human disease research. Nat Rev Genet 12(8):575–582PubMedCrossRefGoogle Scholar
  2. 2.
    Lieschke GJ, Currie PD (2007) Animal models of human disease: zebrafish swim into view. Nat Rev Genet 8(5):353–367PubMedCrossRefGoogle Scholar
  3. 3.
    Lopez Hernandez Y, Yero D, Pinos-Rodriguez JM, Gibert I (2015) Animals devoid of pulmonary system as infection models in the study of lung bacterial pathogens. Front Microbiol 6:38PubMedPubMedCentralGoogle Scholar
  4. 4.
    Markaki M, Tavernarakis N (2010) Modeling human diseases in Caenorhabditis elegans. Biotechnol J 5(12):1261–1276PubMedCrossRefGoogle Scholar
  5. 5.
    Pandey UB, Nichols CD (2011) Human disease models in Drosophila Melanogaster and the role of the fly in therapeutic drug discovery. Pharmacol Rev 63(2):411–436PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Riddle DL, Blumenthal T, Meyer BJ, Priess JR (eds) (1997) C. elegans II, 2nd edn. Cold Spring Harbor Laboratory Press, Cold Spring Harbor (NY)Google Scholar
  7. 7.
    Wood WB (1988) The nematode Caenorhabditis elegans. Cold Spring Harbor Laboratory Press, New YorkGoogle Scholar
  8. 8.
    Sulston JE, Horvitz HR (1977) Post-embryonic cell lineages of the nematode, Caenorhabditis elegans. Dev Biol 56(1):110–156PubMedCrossRefGoogle Scholar
  9. 9.
    Sulston JE, Schierenberg E, White JG, Thomson JN (1983) The embryonic cell lineage of the nematode Caenorhabditis elegans. Dev Biol 100(1):64–119PubMedCrossRefGoogle Scholar
  10. 10.
    Varshney LR, Chen BL, Paniagua E, Hall DH, Chklovskii DB (2011) Structural properties of the Caenorhabditis elegans neuronal network. PLoS Comput Biol 7(2):e1001066PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Samuel BS, Rowedder H, Braendle C, Felix MA, Ruvkun G (2016) Caenorhabditis elegans responses to bacteria from its natural habitats. Proc Natl Acad Sci U S A 113(27):E3941–E3949PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Lewis JA, Fleming JT (1995) Basic culture methods. Methods Cell Biol 48:3–29PubMedCrossRefGoogle Scholar
  13. 13.
    Shaye DD, Greenwald I (2011) OrthoList: a compendium of C. elegans genes with human orthologs. PLoS One 6(5):e20085PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Sonnhammer EL, Durbin R (1997) Analysis of protein domain families in Caenorhabditis elegans. Genomics 46(2):200–216PubMedCrossRefGoogle Scholar
  15. 15.
    Corsi AK, Wightman B, Chalfie M (2015) A transparent window into biology: a primer on Caenorhabditis elegans. Genetics 200(2):387–407PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Strange K (2006) An overview of C. elegans biology. Methods Mol Biol 351:1–11PubMedGoogle Scholar
  17. 17.
    Ellis HM, Horvitz HR (1986) Genetic control of programmed cell death in the nematode C. elegans. Cell 44(6):817–829PubMedCrossRefGoogle Scholar
  18. 18.
    Check E (2002) Worm cast in starring role for Nobel prize. Nature 419(6907):548–549PubMedCrossRefGoogle Scholar
  19. 19.
    Marx J (2002) Nobel prize in physiology or medicine. Tiny worm takes a star turn. Science 298(5593):526PubMedCrossRefGoogle Scholar
  20. 20.
    Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC (1998) Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391(6669):806–811PubMedCrossRefGoogle Scholar
  21. 21.
    Roda A (2010) Discovery and development of the green fluorescent protein, GFP: the 2008 Nobel prize. Anal Bioanal Chem 396(5):1619–1622PubMedCrossRefGoogle Scholar
  22. 22.
    Kricka LJ, Stanley PE (2009) Scientists awarded Nobel prize for work with GFP. Luminescence 24(1):1PubMedCrossRefGoogle Scholar
  23. 23.
    Chalfie M, Tu Y, Euskirchen G, Ward WW, Prasher DC (1994) Green fluorescent protein as a marker for gene expression. Science 263(5148):802–805PubMedCrossRefGoogle Scholar
  24. 24.
    Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75(5):843–854PubMedCrossRefGoogle Scholar
  25. 25.
    Wightman B, Ha I, Ruvkun G (1993) Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell 75(5):855–862PubMedCrossRefGoogle Scholar
  26. 26.
    Mello C, Fire A (1995) DNA transformation. Methods Cell Biol 48:451–482PubMedCrossRefGoogle Scholar
  27. 27.
    Stinchcomb DT, Shaw JE, Carr SH, Hirsh D (1985) Extrachromosomal DNA transformation of Caenorhabditis elegans. Mol Cell Biol 5(12):3484–3496PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Mello CC, Kramer JM, Stinchcomb D, Ambros V (1991) Efficient gene transfer in C.elegans: extrachromosomal maintenance and integration of transforming sequences. EMBO J 10(12):3959–3970PubMedPubMedCentralGoogle Scholar
  29. 29.
    Fire A (1986) Integrative transformation of Caenorhabditis elegans. EMBO J 5(10):2673–2680PubMedPubMedCentralGoogle Scholar
  30. 30.
    Praitis V, Casey E, Collar D, Austin J (2001) Creation of low-copy integrated transgenic lines in Caenorhabditis elegans. Genetics 157(3):1217–1226PubMedPubMedCentralGoogle Scholar
  31. 31.
    Schweinsberg PJ, Grant BD (2013) C. elegans gene transformation by microparticle bombardment. WormBook: the online review of C elegans biology, Pasadena (CA), pp 1–10Google Scholar
  32. 32.
    Dickinson DJ, Goldstein B (2016) CRISPR-based methods for Caenorhabditis elegans genome engineering. Genetics 202(3):885–901PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Kim HM, Colaiacovo MP (2016) CRISPR-Cas9-guided genome engineering in C. elegans. Curr Protoc Mol Biol 115:31 37 1–31 37 18Google Scholar
  34. 34.
    Anderson P (1995) Mutagenesis. Methods Cell Biol 48:31–58PubMedCrossRefGoogle Scholar
  35. 35.
    Kutscher LM, Shaham S (2014) Forward and reverse mutagenesis in C. elegans. WormBook: the online review of C elegans biology, Pasadena (CA), pp 1–26Google Scholar
  36. 36.
    Wang Z, Sherwood DR (2011) Dissection of genetic pathways in C. elegans. Methods Cell Biol 106:113–157PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Fay DS (2013) Classical genetic methods. WormBook: the online review of C elegans biology, Pasadena (CA), pp 1–58Google Scholar
  38. 38.
    Brenner S (1974) The genetics of Caenorhabditis elegans. Genetics 77(1):71–94PubMedPubMedCentralGoogle Scholar
  39. 39.
    Williams BD (1995) Genetic mapping with polymorphic sequence-tagged sites. Methods Cell Biol 48:81–96PubMedCrossRefGoogle Scholar
  40. 40.
    PJ H (2014) Whole genome sequencing and the transformation of C. elegans forward genetics. Methods 68(3):437–440CrossRefGoogle Scholar
  41. 41.
    Hobert O (2010) The impact of whole genome sequencing on model system genetics: get ready for the ride. Genetics 184(2):317–319PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Bessereau JL (2006) Transposons in C. elegans. WormBook: the online review of C elegans biology, Pasadena (CA), pp 1–13Google Scholar
  43. 43.
    Timmons L, Fire A (1998) Specific interference by ingested dsRNA. Nature 395(6705):854PubMedCrossRefGoogle Scholar
  44. 44.
    Fraser AG, Kamath RS, Zipperlen P, Martinez-Campos M, Sohrmann M, Ahringer J (2000) Functional genomic analysis of C. elegans chromosome I by systematic RNA interference. Nature 408(6810):325–330PubMedCrossRefGoogle Scholar
  45. 45.
    Rual JF, Ceron J, Koreth J, Hao T, Nicot AS, Hirozane-Kishikawa T, Vandenhaute J, Orkin SH, Hill DE, van den Heuvel S, Vidal M (2004) Toward improving Caenorhabditis elegans phenome mapping with an ORFeome-based RNAi library. Genome Res 14(10B):2162–2168PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Kennedy S, Wang D, Ruvkun G (2004) A conserved siRNA-degrading RNase negatively regulates RNA interference in C. elegans. Nature 427(6975):645–649PubMedCrossRefGoogle Scholar
  47. 47.
    Simmer F, Tijsterman M, Parrish S, Koushika SP, Nonet ML, Fire A, Ahringer J, Plasterk RH (2002) Loss of the putative RNA-directed RNA polymerase RRF-3 makes C. elegans hypersensitive to RNAi. Curr Biol 12(15):1317–1319PubMedCrossRefGoogle Scholar
  48. 48.
    Consortium CeDM (2012) Large-scale screening for targeted knockouts in the Caenorhabditis elegans genome. G3 2(11):1415–1425CrossRefGoogle Scholar
  49. 49.
    Mitani S (2009) Nematode, an experimental animal in the national BioResource project. Exp Anim 58(4):351–356PubMedCrossRefGoogle Scholar
  50. 50.
    Frokjaer-Jensen C (2015) Transposon-assisted genetic engineering with mos1-mediated single-copy insertion (MosSCI). Methods Mol Biol 1327:49–58PubMedCrossRefGoogle Scholar
  51. 51.
    World Health Statistics 2014 (2015)Google Scholar
  52. 52.
    Detailed Tables for the National Vital Statistics Report (NVSR) (2015) “Deaths: Final Data for 2013”. vol 64Google Scholar
  53. 53.
    Chaudhuri N, Dower SK, Whyte MK, Sabroe I (2005) Toll-like receptors and chronic lung disease. Clin Sci 109(2):125–133PubMedCrossRefGoogle Scholar
  54. 54.
    Cook DN, Pisetsky DS, Schwartz DA (2004) Toll-like receptors in the pathogenesis of human disease. Nat Immunol 5(10):975–979PubMedCrossRefGoogle Scholar
  55. 55.
    Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140(6):883–899PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Takeda K, Akira S (2005) Toll-like receptors in innate immunity. Int Immunol 17(1):1–14PubMedCrossRefGoogle Scholar
  57. 57.
    Kovach MA, Standiford TJ (2011) Toll like receptors in diseases of the lung. Int Immunopharmacol 11(10):1399–1406PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Medvedev AE (2013) Toll-like receptor polymorphisms, inflammatory and infectious diseases, allergies, and cancer. J Interf Cytokine Res 33(9):467–484CrossRefGoogle Scholar
  59. 59.
    Misch EA, Hawn TR (2008) Toll-like receptor polymorphisms and susceptibility to human disease. Clin Sci 114(5):347–360PubMedCrossRefGoogle Scholar
  60. 60.
    Netea MG, Wijmenga C, O'Neill LA (2012) Genetic variation in toll-like receptors and disease susceptibility. Nat Immunol 13(6):535–542PubMedCrossRefGoogle Scholar
  61. 61.
    O'Neill LA (2003) Therapeutic targeting of toll-like receptors for inflammatory and infectious diseases. Curr Opin Pharmacol 3(4):396–403PubMedCrossRefGoogle Scholar
  62. 62.
    Schwartz DA, Cook DN (2005) Polymorphisms of the toll-like receptors and human disease. Clin Infect Dis 7(29):S403–S407Google Scholar
  63. 63.
    Ermolaeva MA, Schumacher B (2014) Insights from the worm: the C. elegans model for innate immunity. Semin Immunol 26(4):303–309PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Irazoqui J, Ausubel F (2010) 99th Dahlem conference on infection, inflammation, and chronic inflammatory disorders: Caenorhabditis elegans as a model to study tissues involved in host immunity and microbial pathogenesis. Clin Exp Immunol 160:48–57PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Pukkila-Worley R, Ausubel FM (2012) Immune defense mechanisms in the Caenorhabditis elegans intestinal epithelium. Curr Opin Immunol 24(1):3–9PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Mahajan-Miklos S, Tan MW, Rahme LG, Ausubel FM (1999) Molecular mechanisms of bacterial virulence elucidated using a Pseudomonas aeruginosa-Caenorhabditis elegans pathogenesis model. Cell 96(1):47–56PubMedCrossRefGoogle Scholar
  67. 67.
    Tan MW, Mahajan-Miklos S, Ausubel FM (1999) Killing of Caenorhabditis elegans by Pseudomonas aeruginosa used to model mammalian bacterial pathogenesis. Proc Natl Acad Sci U S A 96(2):715–720PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Tan MW, Rahme LG, Sternberg JA, Tompkins RG, Ausubel FM (1999) Pseudomonas aeruginosa killing of Caenorhabditis elegans used to identify P. aeruginosa virulence factors. Proc Natl Acad Sci U S A 96(5):2408–2413PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Cohen LB, Troemel ER (2015) Microbial pathogenesis and host defense in the nematode C. elegans. Curr Opin Microbiol 23:94–101PubMedCrossRefGoogle Scholar
  70. 70.
    Diogo J, Bratanich A (2014) The nematode Caenorhabditis elegans as a model to study viruses. Arch Virol 159(11):2843–2851PubMedCrossRefGoogle Scholar
  71. 71.
    Arvanitis M, Glavis-Bloom J, Mylonakis E (2013) Invertebrate models of fungal infection. Biochim Biophys Acta 1832(9):1378–1383PubMedCrossRefGoogle Scholar
  72. 72.
    Darby C (2005) Interactions with microbial pathogens. WormBook: the online review of C elegans biology, Pasadena (CA), pp 1–15Google Scholar
  73. 73.
    Dierking K, Yang W, Schulenburg H (2016) Antimicrobial effectors in the nematode Caenorhabditis elegans: an outgroup to the Arthropoda. Philos Trans R Soc Lond Ser B Biol Sci 371:20150299CrossRefGoogle Scholar
  74. 74.
    Kim DH, Ewbank JJ (2015) Signaling in the innate immune response. WormBook: the online review of C elegans biology, Pasadena (CA), pp 1–51Google Scholar
  75. 75.
    Irazoqui JE, Troemel ER, Feinbaum RL, Luhachack LG, Cezairliyan BO, Ausubel FM (2010) Distinct pathogenesis and host responses during infection of C. elegans by P. aeruginosa and S. aureus. PLoS Pathog 6:e1000982PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Visvikis O, Ihuegbu N, Labed SA, Luhachack LG, Alves AM, Wollenberg AC, Stuart LM, Stormo GD, Irazoqui JE (2014) Innate host defense requires TFEB-mediated transcription of cytoprotective and antimicrobial genes. Immunity 40(6):896–909PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Pastore N, Brady OA, Diab HI, Martina JA, Sun L, Huynh T, Lim JA, Zare H, Raben N, Ballabio A, Puertollano R (2016) TFEB and TFE3 cooperate in the regulation of the innate immune response in activated macrophages. Autophagy 12(8):1240–1258PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Najibi M, Labed SA, Visvikis O, Irazoqui JE (2016) An evolutionarily conserved PLC-PKD-TFEB pathway for host defense. Cell Rep 15(8):1728–1742PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Alper S, McBride SJ, Lackford B, Freedman JH, Schwartz DA (2007) Specificity and complexity of the C. elegans innate immune response. Mol Cell Biol 27(15):5544–5553PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Pulak R (2006) Techniques for analysis, sorting, and dispensing of C. elegans on the COPAS flow-sorting system. Methods Mol Biol 351:275–286PubMedGoogle Scholar
  81. 81.
    Alper S, Laws R, Lackford B, Boyd WA, Dunlap P, Freedman JH, Schwartz DA (2008) Identification of innate immunity genes and pathways using a comparative genomics approach. Proc Natl Acad Sci U S A 105(19):7016–7021PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    De Arras L, Laws R, Leach SM, Pontis K, Freedman JH, Schwartz DA, Alper S (2014) Comparative genomics RNAi screen identifies Eftud2 as a novel regulator of innate immunity. Genetics 197(2):485–496PubMedCrossRefGoogle Scholar
  83. 83.
    De Arras L, Seng A, Lackford B, Keikhaee MR, Bowerman B, Freedman JH, Schwartz DA, Alper S (2013) An evolutionarily conserved innate immunity protein interaction network. J Biol Chem 288(3):1967–1978PubMedCrossRefGoogle Scholar
  84. 84.
    De Arras L, Yang IV, Lackford B, Riches DW, Prekeris R, Freedman JH, Schwartz DA, Alper S (2012) Spatiotemporal inhibition of innate immunity signaling by the Tbc1d23 RAB-GAP. J Immunol 188(6):2905–2913PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Editorial (2003) Whither RNAi? Nat Cell Biol 5(6):489–490CrossRefGoogle Scholar
  86. 86.
    De Arras L, Alper S (2013) Limiting of the innate immune response by SF3A-dependent control of MyD88 alternative mRNA splicing. PLoS Genet 9(10):e1003855PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    O'Connor BP, Danhorn T, De Arras L, Flatley BR, Marcus RA, Farias-Hesson E, Leach SM, Alper S (2015) Regulation of toll-like receptor signaling by the SF3a mRNA splicing complex. PLoS Genet 11(2):e1004932PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Flegal KM, Carroll MD, Kit BK, Ogden CL (2012) Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999–2010. JAMA 307(5):491–497PubMedCrossRefGoogle Scholar
  89. 89.
    Haslam DW, James WP (2005) Obesity. Lancet 366(9492):1197–1209PubMedCrossRefGoogle Scholar
  90. 90.
    Bleich S, Cutler D, Murray C, Adams A (2008) Why is the developed world obese? Annu Rev Public Health 29:273–295PubMedCrossRefGoogle Scholar
  91. 91.
    Ashrafi K (2007) Obesity and the regulation of fat metabolism. WormBook: the online review of C elegans biology, Pasadena (CA), pp 1–20Google Scholar
  92. 92.
    Jones KT, Ashrafi K (2009) Caenorhabditis elegans as an emerging model for studying the basic biology of obesity. Dis Model Mech 2(5–6):224–229PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Zheng J, Greenway FL (2012) Caenorhabditis elegans as a model for obesity research. Int J Obes 36(2):186–194CrossRefGoogle Scholar
  94. 94.
    McKay RM, McKay JP, Avery L, Graff JM (2003) C elegans: a model for exploring the genetics of fat storage. Dev Cell 4(1):131–142PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Ashrafi K, Chang FY, Watts JL, Fraser AG, Kamath RS, Ahringer J, Ruvkun G (2003) Genome-wide RNAi analysis of Caenorhabditis elegans fat regulatory genes. Nature 421(6920):268–272PubMedCrossRefGoogle Scholar
  96. 96.
    Liu Z, Li X, Ge Q, Ding M, Huang X (2014) A lipid droplet-associated GFP reporter-based screen identifies new fat storage regulators in C. elegans. J Genet Genomics 41(5):305–313PubMedCrossRefGoogle Scholar
  97. 97.
    Klass MR (1983) A method for the isolation of longevity mutants in the nematode Caenorhabditis elegans and initial results. Mech Ageing Dev 22(3–4):279–286PubMedCrossRefGoogle Scholar
  98. 98.
    Friedman DB, Johnson TE (1988) A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility. Genetics 118(1):75–86PubMedPubMedCentralGoogle Scholar
  99. 99.
    Friedman DB, Johnson TE (1988) Three mutants that extend both mean and maximum life span of the nematode, Caenorhabditis elegans, define the age-1 gene. J Gerontol 43(4):B102–B109PubMedCrossRefGoogle Scholar
  100. 100.
    Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R (1993) A C. elegans mutant that lives twice as long as wild type. Nature 366(6454):461–464PubMedCrossRefGoogle Scholar
  101. 101.
    Riddle DL, Swanson MM, Albert PS (1981) Interacting genes in nematode dauer larva formation. Nature 290(5808):668–671PubMedCrossRefGoogle Scholar
  102. 102.
    Hu PJ (2007) Dauer. WormBook: the online review of C elegans biology, Pasadena (CA), pp 1–19Google Scholar
  103. 103.
    Albert PS, Riddle DL (1988) Mutants of Caenorhabditis elegans that form dauer-like larvae. Dev Biol 126(2):270–293PubMedCrossRefGoogle Scholar
  104. 104.
    Golden JW, Riddle DL (1984) A pheromone-induced developmental switch in Caenorhabditis elegans: temperature-sensitive mutants reveal a wild-type temperature-dependent process. Proc Natl Acad Sci U S A 81(3):819–823PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Murphy CT, PJ H (2013) Insulin/insulin-like growth factor signaling in C. elegans. WormBook: the online review of C elegans biology, Pasadena (CA), pp 1–43Google Scholar
  106. 106.
    Altintas O, Park S, Lee SJ (2016) The role of insulin/IGF-1 signaling in the longevity of model invertebrates, C. elegans and D. melanogaster. BMB Rep 49(2):81–92PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Giannakou ME, Partridge L (2007) Role of insulin-like signalling in drosophila lifespan. Trends Biochem Sci 32(4):180–188PubMedCrossRefGoogle Scholar
  108. 108.
    Hwangbo DS, Gershman B, MP T, Palmer M, Tatar M (2004) Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body. Nature 429(6991):562–566PubMedCrossRefGoogle Scholar
  109. 109.
    Tatar M, Kopelman A, Epstein D, MP T, Yin CM, Garofalo RS (2001) A mutant drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Science 292(5514):107–110PubMedCrossRefGoogle Scholar
  110. 110.
    Clancy DJ, Gems D, Harshman LG, Oldham S, Stocker H, Hafen E, Leevers SJ, Partridge L (2001) Extension of life-span by loss of CHICO, a drosophila insulin receptor substrate protein. Science 292(5514):104–106PubMedCrossRefGoogle Scholar
  111. 111.
    Kappeler L, De Magalhaes Filho C, Dupont J, Leneuve P, Cervera P, Perin L, Loudes C, Blaise A, Klein R, Epelbaum J, Le Bouc Y, Holzenberger M (2008) Brain IGF-1 receptors control mammalian growth and lifespan through a neuroendocrine mechanism. PLoS Biol 6(10):e254PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Holzenberger M, Dupont J, Ducos B, Leneuve P, Geloen A, Even PC, Cervera P, Le Bouc Y (2003) IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421(6919):182–187PubMedCrossRefGoogle Scholar
  113. 113.
    Brooks-Wilson AR (2013) Genetics of healthy aging and longevity. Hum Genet 132(12):1323–1338PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Chung WH, Dao RL, Chen LK, Hung SI (2010) The role of genetic variants in human longevity. Ageing Res Rev 9(Suppl 1):S67–S78PubMedCrossRefGoogle Scholar
  115. 115.
    Anselmi CV, Malovini A, Roncarati R, Novelli V, Villa F, Condorelli G, Bellazzi R, Puca AA (2009) Association of the FOXO3A locus with extreme longevity in a southern Italian centenarian study. Rejuvenation Res 12(2):95–104PubMedCrossRefGoogle Scholar
  116. 116.
    Daumer C, Flachsbart F, Caliebe A, Schreiber S, Nebel A, Krawczak M (2014) Adjustment for smoking does not alter the FOXO3A association with longevity. Age 36(2):911–921PubMedCrossRefGoogle Scholar
  117. 117.
    Flachsbart F, Caliebe A, Kleindorp R, Blanche H, von Eller-Eberstein H, Nikolaus S, Schreiber S, Nebel A (2009) Association of FOXO3A variation with human longevity confirmed in German centenarians. Proc Natl Acad Sci U S A 106(8):2700–2705PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Kuningas M, Magi R, Westendorp RG, Slagboom PE, Remm M, van Heemst D (2007) Haplotypes in the human Foxo1a and Foxo3a genes; impact on disease and mortality at old age. Eur J Hum Genet 15(3):294–301PubMedCrossRefGoogle Scholar
  119. 119.
    Li Y, Wang WJ, Cao H, Lu J, Wu C, Hu FY, Guo J, Zhao L, Yang F, Zhang YX, Li W, Zheng GY, Cui H, Chen X, Zhu Z, He H, Dong B, Mo X, Zeng Y, Tian XL (2009) Genetic association of FOXO1A and FOXO3A with longevity trait in Han Chinese populations. Hum Mol Genet 18(24):4897–4904PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Lunetta KL, D'Agostino RB Sr, Karasik D, Benjamin EJ, Guo CY, Govindaraju R, Kiel DP, Kelly-Hayes M, Massaro JM, Pencina MJ, Seshadri S, Murabito JM (2007) Genetic correlates of longevity and selected age-related phenotypes: a genome-wide association study in the Framingham study. BMC Med Genet 8(Suppl 1):S13PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Pawlikowska L, Hu D, Huntsman S, Sung A, Chu C, Chen J, Joyner AH, Schork NJ, Hsueh WC, Reiner AP, Psaty BM, Atzmon G, Barzilai N, Cummings SR, Browner WS, Kwok PY, Ziv E, Study of Osteoporotic F (2009) Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity. Aging Cell 8(4):460–472PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Soerensen M, Dato S, Christensen K, McGue M, Stevnsner T, Bohr VA, Christiansen L (2010) Replication of an association of variation in the FOXO3A gene with human longevity using both case-control and longitudinal data. Aging Cell 9(6):1010–1017PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Soerensen M, Nygaard M, Dato S, Stevnsner T, Bohr VA, Christensen K, Christiansen L (2015) Association study of FOXO3A SNPs and aging phenotypes in Danish oldest-old individuals. Aging Cell 14(1):60–66PubMedCrossRefGoogle Scholar
  124. 124.
    Willcox BJ, Donlon TA, He Q, Chen R, Grove JS, Yano K, Masaki KH, Willcox DC, Rodriguez B, Curb JD (2008) FOXO3A genotype is strongly associated with human longevity. Proc Natl Acad Sci U S A 105(37):13987–13992PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Suh Y, Atzmon G, Cho MO, Hwang D, Liu B, Leahy DJ, Barzilai N, Cohen P (2008) Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc Natl Acad Sci U S A 105(9):3438–3442PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Tazearslan C, Huang J, Barzilai N, Suh Y (2011) Impaired IGF1R signaling in cells expressing longevity-associated human IGF1R alleles. Aging Cell 10(3):551–554PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Curran SP, Ruvkun G (2007) Lifespan regulation by evolutionarily conserved genes essential for viability. PLoS Genet 3(4):e56PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Hamilton B, Dong Y, Shindo M, Liu W, Odell I, Ruvkun G, Lee SS (2005) A systematic RNAi screen for longevity genes in C. elegans. Genes Dev 19(13):1544–1555PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Hansen M, Hsu AL, Dillin A, Kenyon C (2005) New genes tied to endocrine, metabolic, and dietary regulation of lifespan from a Caenorhabditis elegans genomic RNAi screen. PLoS Genet 1(1):119–128PubMedCrossRefGoogle Scholar
  130. 130.
    Samuelson AV, Carr CE, Ruvkun G (2007) Gene activities that mediate increased life span of C. elegans insulin-like signaling mutants. Genes Dev 21(22):2976–2994PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Ni Z, Lee SS (2010) RNAi screens to identify components of gene networks that modulate aging in Caenorhabditis elegans. Brief Funct Genomics 9(1):53–64PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Yanos ME, Bennett CF, Kaeberlein M (2012) Genome-wide RNAi longevity screens in Caenorhabditis elegans. Curr Genomics 13(7):508–518PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Longo VD, Antebi A, Bartke A, Barzilai N, Brown-Borg HM, Caruso C, Curiel TJ, de Cabo R, Franceschi C, Gems D, Ingram DK, Johnson TE, Kennedy BK, Kenyon C, Klein S, Kopchick JJ, Lepperdinger G, Madeo F, Mirisola MG, Mitchell JR, Passarino G, Rudolph KL, Sedivy JM, Shadel GS, Sinclair DA, Spindler SR, Suh Y, Vijg J, Vinciguerra M, Fontana L (2015) Interventions to slow aging in humans: are we ready? Aging Cell 14(4):497–510PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Riera CE, Dillin A (2015) Can aging be “drugged”? Nat Med 21(12):1400–1405PubMedCrossRefGoogle Scholar
  135. 135.
    Weber JJ, Sowa AS, Binder T, Hubener J (2014) From pathways to targets: understanding the mechanisms behind polyglutamine disease. Biomed Res Int 2014:701758PubMedPubMedCentralGoogle Scholar
  136. 136.
    Zhao XN, Usdin K (2015) The repeat expansion diseases: the dark side of DNA repair. DNA Repair 32:96–105PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Olejniczak M, Urbanek MO, Krzyzosiak WJ (2015) The role of the immune system in triplet repeat expansion diseases. Mediat Inflamm 2015:873860CrossRefGoogle Scholar
  138. 138.
    Lee DY, McMurray CT (2014) Trinucleotide expansion in disease: why is there a length threshold? Curr Opin Genet Dev 26:131–140PubMedCrossRefGoogle Scholar
  139. 139.
    Iyer RR, Pluciennik A, Napierala M, Wells RD (2015) DNA triplet repeat expansion and mismatch repair. Annu Rev Biochem 84:199–226PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Morley JF, Brignull HR, Weyers JJ, Morimoto RI (2002) The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegans. Proc Natl Acad Sci U S A 99(16):10417–10422PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Brignull HR, Moore FE, Tang SJ, Morimoto RI (2006) Polyglutamine proteins at the pathogenic threshold display neuron-specific aggregation in a pan-neuronal Caenorhabditis elegans model. J Neurosci 26(29):7597–7606PubMedCrossRefGoogle Scholar
  142. 142.
    Faber PW, Alter JR, MacDonald ME, Hart AC (1999) Polyglutamine-mediated dysfunction and apoptotic death of a Caenorhabditis elegans sensory neuron. Proc Natl Acad Sci U S A 96(1):179–184PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Nollen EA, Garcia SM, van Haaften G, Kim S, Chavez A, Morimoto RI, Plasterk RH (2004) Genome-wide RNA interference screen identifies previously undescribed regulators of polyglutamine aggregation. Proc Natl Acad Sci U S A 101(17):6403–6408PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Caldwell GA, Cao S, Sexton EG, Gelwix CC, Bevel JP, Caldwell KA (2003) Suppression of polyglutamine-induced protein aggregation in Caenorhabditis elegans by torsin proteins. Hum Mol Genet 12(3):307–319PubMedCrossRefGoogle Scholar
  145. 145.
    Wang H, Lim PJ, Yin C, Rieckher M, Vogel BE, Monteiro MJ (2006) Suppression of polyglutamine-induced toxicity in cell and animal models of Huntington’s disease by ubiquilin. Hum Mol Genet 15(6):1025–1041PubMedCrossRefGoogle Scholar
  146. 146.
    Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362(4):329–344PubMedCrossRefGoogle Scholar
  147. 147.
    Burns A, Iliffe S (2009) Alzheimer’s disease. BMJ 338:b158PubMedCrossRefGoogle Scholar
  148. 148.
    Dujardin S, Colin M, Buee L (2015) Invited review: animal models of tauopathies and their implications for research/translation into the clinic. Neuropathol Appl Neurobiol 41(1):59–80PubMedCrossRefGoogle Scholar
  149. 149.
    Wentzell J, Kretzschmar D (2010) Alzheimer’s disease and tauopathy studies in flies and worms. Neurobiol Dis 40(1):21–28PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Kraemer BC, Zhang B, Leverenz JB, Thomas JH, Trojanowski JQ, Schellenberg GD (2003) Neurodegeneration and defective neurotransmission in a Caenorhabditis elegans model of tauopathy. Proc Natl Acad Sci U S A 100(17):9980–9985PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Kraemer BC, Burgess JK, Chen JH, Thomas JH, Schellenberg GD (2006) Molecular pathways that influence human tau-induced pathology in Caenorhabditis elegans. Hum Mol Genet 15(9):1483–1496PubMedCrossRefGoogle Scholar
  152. 152.
    Hannan SB, Drager NM, Rasse TM, Voigt A, Jahn TR (2016) Cellular and molecular modifier pathways in tauopathies: the big picture from screening invertebrate models. J Neurochem 137(1):12–25PubMedCrossRefGoogle Scholar
  153. 153.
    Guthrie CR, Schellenberg GD, Kraemer BC (2009) SUT-2 potentiates tau-induced neurotoxicity in Caenorhabditis elegans. Hum Mol Genet 18(10):1825–1838PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Guthrie CR, Greenup L, Leverenz JB, Kraemer BC (2011) MSUT2 Is a determinant of susceptibility to tau neurotoxicity. Hum Mol Genet 20(10):1989–1999PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Alexander AG, Marfil V, Li C (2014) Use of Caenorhabditis elegans as a model to study Alzheimer’s disease and other neurodegenerative diseases. Front Genet 5:279PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Ewald CY, Li C (2010) Understanding the molecular basis of Alzheimer’s disease using a Caenorhabditis elegans model system. Brain Struct Funct 214(2–3):263–283PubMedCrossRefGoogle Scholar
  157. 157.
    Hassan WM, Dostal V, Huemann BN, Yerg JE, Link CD (2015) Identifying Abeta-specific pathogenic mechanisms using a nematode model of Alzheimer’s disease. Neurobiol Aging 36(2):857–866PubMedCrossRefGoogle Scholar
  158. 158.
    Hassan WM, Merin DA, Fonte V, Link CD (2009) AIP-1 ameliorates beta-amyloid peptide toxicity in a Caenorhabditis elegans Alzheimer’s disease model. Hum Mol Genet 18(15):2739–2747PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Link CD (2006) C. elegans models of age-associated neurodegenerative diseases: lessons from transgenic worm models of Alzheimer’s disease. Exp Gerontol 41(10):1007–1013PubMedCrossRefGoogle Scholar
  160. 160.
    Wu Y, Wu Z, Butko P, Christen Y, Lambert MP, Klein WL, Link CD, Luo Y (2006) Amyloid-beta-induced pathological behaviors are suppressed by Ginkgo Biloba extract EGb 761 and ginkgolides in transgenic Caenorhabditis elegans. J Neurosci 26(50):13102–13113PubMedCrossRefGoogle Scholar
  161. 161.
    Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, CE Y, Jondro PD, Schmidt SD, Wang K et al (1995) Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science 269(5226):973–977PubMedCrossRefGoogle Scholar
  162. 162.
    Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holman K, Tsuda T et al (1995) Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature 376(6543):775–778PubMedCrossRefGoogle Scholar
  163. 163.
    Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, Tsuda T, Mar L, Foncin JF, Bruni AC, Montesi MP, Sorbi S, Rainero I, Pinessi L, Nee L, Chumakov I, Pollen D, Brookes A, Sanseau P, Polinsky RJ, Wasco W, Da Silva HA, Haines JL, Perkicak-Vance MA, Tanzi RE, Roses AD, Fraser PE, Rommens JM, St George-Hyslop PH (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375(6534):754–760PubMedCrossRefGoogle Scholar
  164. 164.
    Levitan D, Doyle TG, Brousseau D, Lee MK, Thinakaran G, Slunt HH, Sisodia SS, Greenwald I (1996) Assessment of normal and mutant human presenilin function in Caenorhabditis elegans. Proc Natl Acad Sci U S A 93(25):14940–14944PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Levitan D, Greenwald I (1995) Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer’s disease gene. Nature 377(6547):351–354PubMedCrossRefGoogle Scholar
  166. 166.
    Wong PC, Zheng H, Chen H, Becher MW, Sirinathsinghji DJ, Trumbauer ME, Chen HY, Price DL, Van der Ploeg LH, Sisodia SS (1997) Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm. Nature 387(6630):288–292PubMedCrossRefGoogle Scholar
  167. 167.
    Francis R, McGrath G, Zhang J, Ruddy DA, Sym M, Apfeld J, Nicoll M, Maxwell M, Hai B, Ellis MC, Parks AL, Xu W, Li J, Gurney M, Myers RL, Himes CS, Hiebsch R, Ruble C, Nye JS, Curtis D (2002) Aph-1 and pen-2 are required for notch pathway signaling, gamma-secretase cleavage of betaAPP, and presenilin protein accumulation. Dev Cell 3(1):85–97PubMedCrossRefGoogle Scholar
  168. 168.
    Goutte C, Tsunozaki M, Hale VA, Priess JR (2002) APH-1 is a multipass membrane protein essential for the notch signaling pathway in Caenorhabditis elegans embryos. Proc Natl Acad Sci U S A 99(2):775–779PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Luo WJ, Wang H, Li H, Kim BS, Shah S, Lee HJ, Thinakaran G, Kim TW, Yu G, Xu H (2003) PEN-2 and APH-1 coordinately regulate proteolytic processing of presenilin 1. J Biol Chem 278(10):7850–7854PubMedCrossRefGoogle Scholar
  170. 170.
    Samii A, Nutt JG, Ransom BR (2004) Parkinson’s disease. Lancet 363(9423):1783–1793PubMedCrossRefGoogle Scholar
  171. 171.
    Shulman JM, De Jager PL, Feany MB (2011) Parkinson’s disease: genetics and pathogenesis. Annu Rev Pathol 6:193–222PubMedCrossRefGoogle Scholar
  172. 172.
    Davie CA (2008) A review of Parkinson’s disease. Br Med Bull 86:109–127PubMedCrossRefGoogle Scholar
  173. 173.
    Atik A, Stewart T, Zhang J (2016) Alpha-synuclein as a biomarker for Parkinson’s disease. Brain Pathol 26(3):410–418PubMedCrossRefGoogle Scholar
  174. 174.
    Schulz-Schaeffer WJ (2010) The synaptic pathology of alpha-synuclein aggregation in dementia with Lewy bodies, Parkinson’s disease and Parkinson’s disease dementia. Acta Neuropathol 120(2):131–143PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Chege PM, McColl G (2014) Caenorhabditis elegans: a model to investigate oxidative stress and metal dyshomeostasis in Parkinson’s disease. Front Aging Neurosci 6:89PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    van Ham TJ, Thijssen KL, Breitling R, Hofstra RM, Plasterk RH, Nollen EA (2008) C. elegans model identifies genetic modifiers of alpha-synuclein inclusion formation during aging. PLoS Genet 4(3):e1000027PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Hamamichi S, Rivas RN, Knight AL, Cao S, Caldwell KA, Caldwell GA (2008) Hypothesis-based RNAi screening identifies neuroprotective genes in a Parkinson’s disease model. Proc Natl Acad Sci U S A 105(2):728–733PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Kuwahara T, Koyama A, Koyama S, Yoshina S, Ren CH, Kato T, Mitani S, Iwatsubo T (2008) A systematic RNAi screen reveals involvement of endocytic pathway in neuronal dysfunction in alpha-synuclein transgenic C. elegans. Hum Mol Genet 17(19):2997–3009PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2018

Authors and Affiliations

  1. 1.Department of BiologyNortheastern UniversityBostonUSA
  2. 2.Department of Biomedical Research, Center for Genes, Environment and HealthNational Jewish HealthDenverUSA
  3. 3.Department of Immunology and MicrobiologyUniversity of Colorado School of MedicineAuroraUSA

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