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C. elegans as a Model for Synucleinopathies and Other Neurodegenerative Diseases: Tools and Techniques

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Alpha-Synuclein

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1948))

Abstract

Caenorhabditis elegans is widely used to investigate biological processes related to health and disease. Multiple C. elegans models for human neurodegenerative diseases do exist, including those expressing human α-synuclein. Even though these models do not feature all pathological and molecular hallmarks of the disease they mimic, they allow for the identification and dissection of molecular pathways that are involved. In line with this, genetic screens have yielded multiple modifiers of proteotoxicity in C. elegans models for neurodegenerative diseases. Here, we describe a set of common screening approaches and tools that can be used to study synucleinopathies and other neurodegenerative diseases in C. elegans. RNA interference and mutagenesis screens can be used to find genes that affect proteotoxicity, while relatively simple molecular, cellular (fractionation studies), metabolic (respiration studies), and behavioral (thrashing and crawling) readouts can be used to study the effects of disease proteins and modifiers more closely.

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References

  1. Morley JF, Brignull HR, Weyers JJ et al (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 99:10417–10422

    Article  PubMed  PubMed Central  Google Scholar 

  2. Dillin A, Hsu AL, Arantes-Oliveira N et al (2002) Rates of behavior and aging specified by mitochondrial function during development. Science 298:2398–2401

    Article  CAS  PubMed  Google Scholar 

  3. Lee SS, Kennedy S, Tolonen AC et al (2003) DAF-16 target genes that control C. elegans life-span and metabolism. Science 300:644–647

    Article  CAS  PubMed  Google Scholar 

  4. Nollen EAA, Garcia SM, van Haaften G et al (2004) Genome-wide RNA interference screen identifies previously undescribed regulators of polyglutamine aggregation. Proc Natl Acad Sci U S A 101:6403–6408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kim Y, Sun H (2007) Functional genomic approach to identify novel genes involved in the regulation of oxidative stress resistance and animal lifespan. Aging Cell 6:489–503

    Article  CAS  PubMed  Google Scholar 

  6. Van Ham TJ, Thijssen KL, Breitling R et al (2008) C. elegans model identifies genetic modifiers of α-synuclein inclusion formation during aging. PLoS Genet 4:e1000027–e1000011

    Article  PubMed  PubMed Central  Google Scholar 

  7. Habchi J, Arosio P, Perni M et al (2016) An anticancer drug suppresses the primary nucleation reaction that initiates the production of the toxic A 42 aggregates linked with Alzheimer’s disease. Sci Adv 2:e1501244–e1501244

    Article  PubMed  PubMed Central  Google Scholar 

  8. Arvanitis M, Li DD, Lee K et al (2013) Apoptosis in C. elegans: lessons for cancer and immunity. Front Cell Infect Microbiol 3:67

    Article  PubMed  PubMed Central  Google Scholar 

  9. Jorgensen EM, Mango SE (2002) The art and design of genetic screens: caenorhabditis elegans. Nat Rev Genet 3:356–369

    Article  CAS  PubMed  Google Scholar 

  10. Hamilton B, Dong Y, Shindo M et al (2005) A systematic RNAi screen for longevity genes in C. elegans. Genes Dev 19:1544–1555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Van der Goot AT, Zhu W, Vázquez-Manrique RP et al (2012) Delaying aging and the aging-associated decline in protein homeostasis by inhibition of tryptophan degradation. Proc Natl Acad Sci U S A 109:14912–14917

    Article  PubMed  PubMed Central  Google Scholar 

  12. Van Ham TJ, Holmberg MA, van der Goot AT et al (2010) Identification of MOAG-4/SERF as a regulator of age-related proteotoxicity. Cell 142:601–612

    Article  PubMed  Google Scholar 

  13. Lai CH, Chou CY, Chang LY et al (2000) Identification of novel human genes evolutionarily conserved in Caenorhabditis elegans by comparative proteomics. Genome Res 10:703–713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Shaye DD, Greenwald I (2011) OrthoList: a compendium of C. elegans genes with human orthologs. PLoS One 6(5):e20085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Faber PW, Alter JR, Macdonald ME et al (1999) Polyglutamine-mediated dysfunction and apoptotic death of a Caenorhabditis elegans sensory neuron. Proc Natl Acad Sci U S A 96:179–184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lasko M, Vartianen S, Moilanen AM et al (2003) Dopaminergic neuronal loss and motor deficits in Caenorhabditis elegans overexpressing human alpha-synuclein. J Neurosci 86:165–172

    Google Scholar 

  17. Wang J, Farr GW, Hall DH et al (2009) An ALS-linked mutant SOD1 produces a locomotor defect associated with aggregation and synaptic dysfunction when expressed in neurons of Caenorhabditis elegans. PLoS Genet 5:e1000350

    Article  PubMed  PubMed Central  Google Scholar 

  18. Ash PE, Zhang YJ, Roberts CM et al (2010) Neurotoxic effects of TDP-43 overexpression in C. elegans. Hum Mol Genet 19:3206–3218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Treusch S, Hamamichi S, Goodman JL (2011) Functional links between Aβ toxicity, endocytic trafficking and Alzheimer’s disease risk factors in yeast. Science 334(6060):1241–1245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Martinez BA, Petersen DA, Gaeta AL et al (2017) Dysregulation of the mitochondrial unfolded protein response induces non-apoptotic dopaminergic neurodegeneration in C. elegans models of Parkinson's disease. J Neurosci 37(46):11085–11100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Link CD (1995) Expression of human beta-amyloid peptide in transgenic Caenorhabditis elegans. Proc Natl Acad Sci U S A 92:9368–9372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ben-Zvi A, Miller EA, Morimoto RI (2009) Collapse of proteostasis represents an early molecular event in Caenorhabditis elegans aging. Proc Natl Acad Sci U S A 106:14914–14919

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yano H, Baranov SV, Baranova OV et al (2014) Inhibition of mitochondrial protein important by mutant huntingtin. Nat Neurosci 17(6):822–831

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wang W, Wang L, Lu J et al (2016) The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity. Nat Med 22:869–878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ryan T, Bamm VV, Stykel MG et al (2018) Cardiolipin exposure on the outer mitochondrial membrane modulates α-synuclein. Nat Commun 9:817

    Article  PubMed  PubMed Central  Google Scholar 

  26. Ferreira IL, Resende R, Ferreiro E et al (2010) Multiple defects in energy metabolism in Alzheimer’s disease. Curr Drug Targets 11:1193–1206

    Article  CAS  PubMed  Google Scholar 

  27. Jarrett SF, Lewin AS, Boulton ME (2010) The importance of mitochondria in age-related and inherited eye disorders. Ophthalmic Res 44:179–190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kawamata H, Manfredi G (2010) Mitochondrial dysfunction and intracellular calcium dysregulation in ALS. Mech Ageing Dev 131:517–526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ren J, Pulakat L, Whaley-Connell A et al (2010) Mitochondrial biogenesis in the metabolic syndrome and cardiovascular disease. J Mol Med 88:993–1001

    Article  CAS  PubMed  Google Scholar 

  30. Koopman M, Michels H, Dancy BM et al (2016) A screening-based platform for the assessment of cellular respiration in Caenorhabditis elegans. Nat Protoc 11(10):1798–1816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kamath RS, Ahringer J (2003) Genome-wide RNAi screening in Caenorhabditis elegans. Methods 30(4):313–321

    Article  CAS  PubMed  Google Scholar 

  32. Rual JF, Ceron J, Koreth J et al (2004) Toward improving Caenorhabditis elegans phenome mapping with an ORFeome-based RNAi library. Genome Res 14(10b):2162–2168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Perni M, Challa PK, Kirkegaard JB et al (2018) Massively parallel C. elegans tracking provides multi-dimensional fingerprints for phenotypic discovery. J Neurosci Methods 306:57–67. https://doi.org/10.1016/j.jneumeth.2018.02.005

    Article  PubMed  Google Scholar 

  34. Stiernagle T (2006) Maintenance of C. elegans. In: Wormbook (ed) The C. elegans Research Community

    Google Scholar 

  35. Corsi AK, Wightman B, Chalfie M (2015) A Transparent window into biology: a primer on Caenorhabditis elegans. In: Wormbook (ed) The C. elegans Research Community

    Google Scholar 

  36. Brenner S (1974) The genetics of Caenorhabditis elegans. Genetics 77:71–94

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Wicks SR, Yeh RT, Gish WR et al (2001) Rapig gene mapping in Caenorhabditis elegans using a high density polymorphism map. Nat Genet 28(2):160–164

    Article  CAS  PubMed  Google Scholar 

  38. Swan KA, Curtis DE, McKusick KB et al (2002) High-throughput gene mapping in Caenorhabditis elegans. Genome Res 12(7):1100–1105

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Sin O, Michels H, Nollen EA (2014) Genetic screens in Caenorhabditis elegans models for neurodegenerative diseases. Biochim Biophys Acta 1842(10):1951–1959

    Article  CAS  PubMed  Google Scholar 

  40. Herndon LA, Schmeissner PJ, Dudaronek JM et al (2002) Stochastic and genetic factors influence tissue-specific decline in ageing C. elegans. Nature 419:808–814

    Article  CAS  PubMed  Google Scholar 

  41. Augustin H, Partridge L (2009) Invertebrate models of age-related muscle degeneration. Biochim Biophys Acta 1790:1084–1094

    Article  CAS  PubMed  Google Scholar 

  42. Pierce-Shimomura JT, Chen BL, Mun JJ (2008) Genetic analysis of crawling and swimming locomotory patterns in C. elegans. Proc Natl Acad Sci U S A 105(52):20982–20987

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kontopoulos E, Parvin JD, Feany MB (2006) Alpha-synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity. Hum Mol Genet 15(20):3012–3023

    Article  CAS  PubMed  Google Scholar 

  44. Barmada SJ, Skibinski G, Korb E et al (2010) Cytoplasmic mislocalization of TDP-43 is toxic to neurons and enhanced by a mutation associated with familial ALS. J Neurosci 30(2):639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Chen F, Hersh BM, Conradt B et al (2000) Translocation of C. elegans CED-4 to nuclear membranes during programmed cell death. Science 287(5457):1485–1489

    Article  CAS  PubMed  Google Scholar 

  46. La Rocca G, Burgio G, Corona DF (2007) A protein nuclear extract from D. melanogaster larval tissues. Fly (Austin) 1(6):343–345

    Article  Google Scholar 

  47. Mitchell DH, Stiles JW, Santelli J et al (1979) Synchronous growth and aging of Caenorhabditis elegans in the presence of fluorodeoxyuridine. J Gerontol 34:28–36

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Ellen A. A. Nollen .

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Koopman, M., Seinstra, R.I., Nollen, E.A.A. (2019). C. elegans as a Model for Synucleinopathies and Other Neurodegenerative Diseases: Tools and Techniques. In: Bartels, T. (eds) Alpha-Synuclein. Methods in Molecular Biology, vol 1948. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-9124-2_9

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  • DOI: https://doi.org/10.1007/978-1-4939-9124-2_9

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  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-9123-5

  • Online ISBN: 978-1-4939-9124-2

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