Skip to main content
SpringerLink
Log in

Alternative Models of Prion Diseases

  • Chapter
  • First Online:
Prions and Diseases

  • 1495 Accesses

Abstract

Prion diseases encompass a diverse group of lethal neurodegenerative disorders associated with the accumulation of misfolded conformers of the prion protein (PrP) in brain neurons. Modeling these diseases in mice and hamsters has led to major advances in our understanding of prion transmission and pathogenesis. However, laboratory rodents are also expensive, time-consuming, and limiting for systematic studies. Genetically tractable animal models, such as the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and the zebrafish Danio rerio, have recently made significant contributions to PrP pathogenesis. Here, we discuss recent applications of these three nonmammalian models to various relevant areas, including PrP processing, trafficking, misfolding, neurotoxicity, as well as unraveling its elusive endogenous function. Now that these alternative models have staked a claim on PrP biology, we anticipate that they will expand their range of applications and contributions in the next few years, including the generation of nonmammalian models of prion transmissibility.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 229.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 299.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 299.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

CFP:

Cyan fluorescent protein

GFP:

Green fluorescent protein

GSS:

Gerstmann–Sträussler–Scheinker

Hsp70:

Heat shock protein 70

PrP:

Prion protein

PrPC :

Cellular PrP

PrPSc :

Scrapie PrP

SCA:

Spinocerebellar ataxia

WT:

Wild type

References

  • Abid K, Morales R, Soto C (2010) Cellular factors implicated in prion replication. FEBS Lett 584:2409–2414

    Article  PubMed  CAS  Google Scholar 

  • Aguzzi A, Baumann F, Bremer J (2008) The prion’s elusive reason for being. Annu Rev Neurosci 31:439–477

    Article  PubMed  CAS  Google Scholar 

  • Auluck PK, Bonini NM (2002) Pharmacological prevention of Parkinson disease in Drosophila. Nat Med 8:1185–1186

    Article  PubMed  CAS  Google Scholar 

  • Auluck PK, Chan HY, Trojanowski JQ, Lee VM, Bonini NM (2002) Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson’s disease. Science 295:865–868

    Article  PubMed  CAS  Google Scholar 

  • Bargmann CI, Hartwieg E, Horvitz HR (1993) Odorant-selective genes and neurons mediate olfaction in C. elegans. Cell 74:515–527

    Article  PubMed  CAS  Google Scholar 

  • Bellen HJ, Tong C, Tsuda H (2010) 100 years of Drosophila research and its impact on vertebrate neuroscience: a history lesson for the future. Nat Rev Neurosci 11:514–522

    Article  PubMed  CAS  Google Scholar 

  • Bizat N, Peyrin JM, Haik S, Cochois V, Beaudry P et al (2010) Neuron dysfunction is induced by prion protein with an insertional mutation via a Fyn kinase and reversed by sirtuin activation in Caenorhabditis elegans. J Neurosci 30:5394–5403

    Article  PubMed  CAS  Google Scholar 

  • Brandner S, Isenmann S, Raeber A, Fischer M, Sailer A et al (1996) Normal host prion protein necessary for scrapie-induced neurotoxicity. Nature 379:339–343

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Brenner S (2009) In the beginning was the worm. Genetics 182:413–415

    Article  PubMed  Google Scholar 

  • Chen L, Feany MB (2005) Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease. Nat Neurosci 8:657–663

    Article  PubMed  CAS  Google Scholar 

  • Chen HK, Fernandez-Funez P, Acevedo SF, Lam YC, Kaytor MD et al (2003) Interaction of Akt-phosphorylated ataxin-1 with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia type 1. Cell 113:457–468

    Article  PubMed  CAS  Google Scholar 

  • Choi JK, Jeon YC, Lee DW, Oh JM, Lee HP et al (2010) A Drosophila model of GSS syndrome suggests defects in active zones are responsible for pathogenesis of GSS syndrome. Hum Mol Genet 19:4474–4489

    Article  PubMed  CAS  Google Scholar 

  • Colby DW, Prusiner SB (2011) Prions. Cold Spring Harb Perspect Biol 3:a006833

    Article  PubMed  Google Scholar 

  • Cotto E, Andre M, Forgue J, Fleury HJ, Babin PJ (2005) Molecular characterization, phylogenetic relationships, and developmental expression patterns of prion genes in zebrafish (Danio rerio). FEBS J 272:500–513

    Article  PubMed  CAS  Google Scholar 

  • Deleault NR, Dolph PJ, Feany MB, Cook ME, Nishina K et al (2003) Post-transcriptional suppression of pathogenic prion protein expression in Drosophila neurons. J Neurochem 85:1614–1623

    Article  PubMed  CAS  Google Scholar 

  • Dimitriadi M, Hart AC (2010) Neurodegenerative disorders: insights from the nematode Caenorhabditis elegans. Neurobiol Dis 40:4–11

    Article  PubMed  CAS  Google Scholar 

  • Feany MB, Bender WW (2000) A Drosophila model of Parkinson’s disease. Nature 404:394–398

    Article  PubMed  CAS  Google Scholar 

  • Fernandez-Funez P, Nino-Rosales ML, de Gouyon B, She WC, Luchak JM et al (2000) Identification of genes that modify ataxin-1-induced neurodegeneration. Nature 408:101–106

    Article  PubMed  CAS  Google Scholar 

  • Fernandez-Funez P, Casas-Tinto S, Zhang Y, Gomez-Velazquez M, Morales-Garza MA et al (2009) In vivo generation of neurotoxic prion protein: role for hsp70 in accumulation of misfolded isoforms. PLoS Genet 5:e1000507

    Article  PubMed  Google Scholar 

  • Fernandez-Funez P, Zhang Y, Casas-Tinto S, Xiao X, Zou WQ et al (2010) Sequence-dependent prion protein misfolding and neurotoxicity. J Biol Chem 285:36897–36908

    Article  PubMed  CAS  Google Scholar 

  • Fernandez-Funez P, Zhang Y, Sanchez-Garcia J, Jensen K, Zou W et al (2011) Pulling rabbits to reveal the secrets of the prion protein. Commun Integr Biol 4(3):262–6

    Article  PubMed  CAS  Google Scholar 

  • Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE et al (1998) Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391:806–811

    Article  PubMed  CAS  Google Scholar 

  • Fleisch VC, Ritzel G, Pillay L, Wang H, Waskiewicz A et al (2011) Uncovering the physiological role of Prion protein in a Zebrafish PrP mutant. Prion 5:43

    Google Scholar 

  • Gavin BA, Dolph MJ, Deleault NR, Geoghegan JC, Khurana V et al (2006) Accelerated accumulation of misfolded prion protein and spongiform degeneration in a Drosophila model of Gerstmann-Straussler-Scheinker syndrome. J Neurosci 26:12408–12414

    Article  PubMed  CAS  Google Scholar 

  • Graveley BR, Brooks AN, Carlson JW, Duff MO, Landolin JM et al (2011) The developmental transcriptome of Drosophila melanogaster. Nature 471:473–479

    Article  PubMed  CAS  Google Scholar 

  • Groschup MH, Buschmann A (2008) Rodent models for prion diseases. Vet Res 39:32

    Article  PubMed  Google Scholar 

  • Guo S (2004) Linking genes to brain, behavior and neurological diseases: what can we learn from zebrafish? Genes Brain Behav 3:63–74

    Article  PubMed  CAS  Google Scholar 

  • Harris DA, True HL (2006) New insights into prion structure and toxicity. Neuron 50:353–357

    Article  PubMed  CAS  Google Scholar 

  • Hill AF, Collinge J (2003) Subclinical prion infection. Trends Microbiol 11:578–584

    Article  PubMed  CAS  Google Scholar 

  • Ingham PW (2009) The power of the zebrafish for disease analysis. Hum Mol Genet 18:R107–112

    Article  PubMed  CAS  Google Scholar 

  • Jackson GR, Salecker I, Dong X, Yao X, Arnheim N et al (1998) Polyglutamine-expanded human huntingtin transgenes induce degeneration of Drosophila photoreceptor neurons. Neuron 21:633–642

    Article  PubMed  CAS  Google Scholar 

  • Kaletta T, Hengartner MO (2006) Finding function in novel targets: C. elegans as a model organism. Nat Rev Drug Discov 5:387–398

    Article  PubMed  CAS  Google Scholar 

  • Khan MQ, Sweeting B, Mulligan VK, Arslan PE, Cashman NR et al (2010) Prion disease susceptibility is affected by beta-structure folding propensity and local side-chain interactions in PrP. Proc Natl Acad Sci U S A 107:19808–19813

    Article  PubMed  CAS  Google Scholar 

  • Lasmezas CI, Deslys JP, Robain O, Jaegly A, Beringue V et al (1997) Transmission of the BSE agent to mice in the absence of detectable abnormal prion protein. Science 275:402–405

    Article  PubMed  CAS  Google Scholar 

  • Malaga-Trillo E, Sempou E (2009) PrPs: proteins with a purpose: lessons from the zebrafish. Prion 3:129–133

    Article  PubMed  Google Scholar 

  • Malaga-Trillo E, Solis GP, Schrock Y, Geiss C, Luncz L et al (2009) Regulation of embryonic cell adhesion by the prion protein. PLoS Biol 7:e55

    Article  PubMed  Google Scholar 

  • Malaga-Trillo E, Salta E, Figueras A, Panagiotidis C, Sklaviadis T (2010) Fish models in prion biology: underwater issues. Biochim Biophys Acta 1812:402–414

    PubMed  Google Scholar 

  • Malaga-Trillo E, Sempou E, Jechow K (2011) Using zebrafish to stufy PrP function and the molecular basis of neurodegeneration. Prion 5:3

    Google Scholar 

  • Mange A, Milhavet O, Umlauf D, Harris D, Lehmann S (2002) PrP-dependent cell adhesion in N2a neuroblastoma cells. FEBS Lett 514:159–162

    Article  PubMed  CAS  Google Scholar 

  • Markaki M, Tavernarakis N (2010) Modeling human diseases in Caenorhabditis elegans. Biotechnol J 5:1261–1276

    Article  PubMed  CAS  Google Scholar 

  • Matthews KA, Kaufman TC, Gelbart WM (2005) Research resources for Drosophila: the expanding universe. Nat Rev Genet 6:179–193

    Article  PubMed  CAS  Google Scholar 

  • Mouillet-Richard S, Ermonval M, Chebassier C, Laplanche JL, Lehmann S et al (2000) Signal transduction through prion protein. Science 289:1925–1928

    Article  PubMed  CAS  Google Scholar 

  • Nourizadeh-Lillabadi R, Seilo Torgersen J, Vestrheim O, Konig M, Alestrom P et al (2010) Early embryonic gene expression profiling of zebrafish prion protein (Prp2) morphants. PLoS One 5:e13573

    Article  PubMed  Google Scholar 

  • Pandey UB, Nichols CD (2011) Human disease models in Drosophila melanogaster and the role of the fly in therapeutic drug discovery. Pharmacol Rev 63:411–436

    Article  PubMed  CAS  Google Scholar 

  • Park KW, Li L (2008) Cytoplasmic expression of mouse prion protein causes severe toxicity in Caenorhabditis elegans. Biochem Biophys Res Commun 372:697–702

    Article  PubMed  CAS  Google Scholar 

  • Park Y, Kim W, Kim AY, Choi HJ, Choi JK et al (2011) Normal prion protein in Drosophila enhances the toxicity of pathogenic polyglutamine proteins and alters susceptibility to oxidative and autophagy signaling modulators. Biochem Biophys Res Commun 404:638–645

    Article  PubMed  CAS  Google Scholar 

  • Pfeiffer BD, Ngo TT, Hibbard KL, Murphy C, Jenett A et al (2010) Refinement of tools for targeted gene expression in Drosophila. Genetics 186:735–755

    Article  PubMed  CAS  Google Scholar 

  • Prusiner SB (1998) Prions. Proc Natl Acad Sci U S A 95:13363–13383

    Article  PubMed  CAS  Google Scholar 

  • Raeber AJ, Muramoto T, Kornberg TB, Prusiner SB (1995) Expression and targeting of Syrian hamster prion protein induced by heat shock in transgenic Drosophila melanogaster. Mech Dev 51:317–327

    Article  PubMed  CAS  Google Scholar 

  • Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S et al (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 36:585–595

    Article  PubMed  CAS  Google Scholar 

  • Rincon-Limas DE, Casas-Tinto S, Fernandez-Funez P (2010) Exploring prion protein biology in flies: genetics and beyond. Prion 4:1–8

    Article  PubMed  CAS  Google Scholar 

  • Rincon-Limas D, Jensen K, Fernandez Funez A (2012) Drosophila models of proteinopathies: the little fly that could. Curr Pharm Des 18:1108–1122

    Google Scholar 

  • Rinkwitz S, Mourrain P, Becker TS (2011) Zebrafish: an integrative system for neurogenomics and neurosciences. Prog Neurobiol 93:231–243

    Article  PubMed  Google Scholar 

  • Rivera-Milla E, Oidtmann B, Panagiotidis CH, Baier M, Sklaviadis T et al (2006) Disparate evolution of prion protein domains and the distinct origin of Doppel- and prion-related loci revealed by fish-to-mammal comparisons. FASEB J 20:317–319

    PubMed  CAS  Google Scholar 

  • Roucou X, Gains M, LeBlanc AC (2004) Neuroprotective functions of prion protein. J Neurosci Res 75:153–161

    Article  PubMed  CAS  Google Scholar 

  • Sandberg MK, Al-Doujaily H, Sharps B, Clarke AR, Collinge J (2011) Prion propagation and toxicity in vivo occur in two distinct mechanistic phases. Nature 470:540–542

    Article  PubMed  CAS  Google Scholar 

  • Santuccione A, Sytnyk V, Leshchyns’ka I, Schachner M (2005) Prion protein recruits its neuronal receptor NCAM to lipid rafts to activate p59fyn and to enhance neurite outgrowth. J Cell Biol 169:341–354

    Article  PubMed  CAS  Google Scholar 

  • Soto C, Satani N (2010) The intricate mechanisms of neurodegeneration in prion diseases. Trends Mol Med 17:14–24

    Google Scholar 

  • Steele AD, Lindquist S, Aguzzi A (2007) The prion protein knockout mouse: a phenotype under challenge. Prion 1:83–93

    Article  PubMed  Google Scholar 

  • Steffan JS, Bodai L, Pallos J, Poelman M, McCampbell A et al (2001) Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413:739–743

    Article  PubMed  CAS  Google Scholar 

  • Steinhilb ML, Dias-Santagata D, Fulga TA, Felch DL, Feany MB (2007) Tau phosphorylation sites work in concert to promote neurotoxicity in vivo. Mol Biol Cell 18:5060–5068

    Article  PubMed  CAS  Google Scholar 

  • Sulston JE, Schierenberg E, White JG, Thomson JN (1983) The embryonic cell lineage of the nematode Caenorhabditis elegans. Dev Biol 100:64–119

    Article  PubMed  CAS  Google Scholar 

  • Supattapone S (2004) Prion protein conversion in vitro. J Mol Med (Berl) 82:348–356

    Article  CAS  Google Scholar 

  • Suzuki T, Kurokawa T, Hashimoto H, Sugiyama M (2002) cDNA sequence and tissue expression of Fugu rubripes prion protein-like: a candidate for the teleost orthologue of tetrapod PrPs. Biochem Biophys Res Commun 294:912–917

    Article  PubMed  CAS  Google Scholar 

  • van der Kamp MW, Daggett V (2009) The consequences of pathogenic mutations to the human prion protein. Protein Eng Des Sel 22:461–468

    Article  PubMed  Google Scholar 

  • Venken KJ, Bellen HJ (2007) Transgenesis upgrades for Drosophila melanogaster. Development 134:3571–3584

    Article  PubMed  CAS  Google Scholar 

  • Warrick JM, Paulson HL, Gray-Board GL, Bui QT, Fischbeck KH et al (1998) Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila. Cell 93:939–949

    Article  PubMed  CAS  Google Scholar 

  • Warrick JM, Chan HY, Gray-Board GL, Chai Y, Paulson HL et al (1999) Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nat Genet 23:425–428

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Dr. Liming Li (Northwestern University, IL) for kindly providing the worm images. This work was supported by the NIH grant DP2OD002721 to PF-F, star-up funding from the Department of Neurology (UF) to PF-F and DER-L, and funding from Deutsche Forschungsgemeinschaft (TR-SFB11), the TSE Platform of the MWK, and the FCI to EM-T.

Author information

Authors and Affiliations

  1. Departments of Neurology and Neurosciences, McKnight Brain Institute, University of Florida, 1001149 S. Newell Drive, Gainesville, FL, 32611-0236, USA

    Pedro Fernandez-Funez Ph.D. & Diego E. Rincon-Limas Ph.D.

  2. Department of Biology, University of Konstanz, Konstanz, Germany

    Edward Málaga-Trillo

Authors
  1. Pedro Fernandez-Funez Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Edward Málaga-Trillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Diego E. Rincon-Limas Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pedro Fernandez-Funez Ph.D. .

Editor information

Editors and Affiliations

  1. , Department of Pathology, Case Western Reserve University School o, 2085 Adelbert Road, Cleveland, 44106, Ohio, USA

    Wen-Quan Zou

  2. , Department of Neuropathology, Case Western Reserve University School o, 2085 Adelbert Road, Cleveland, 44106, Ohio, USA

    Pierluigi Gambetti

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Fernandez-Funez, P., Málaga-Trillo, E., Rincon-Limas, D.E. (2013). Alternative Models of Prion Diseases. In: Zou, WQ., Gambetti, P. (eds) Prions and Diseases. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5338-3_12

Download citation

Publish with us

Policies and ethics

Search

Navigation