Skip to main content
SpringerLink
Log in
Book cover

Techniques in Prion Research pp 176–197Cite as

Birkhäuser

Cytotoxicity of PrP Peptides

  • Chapter

Part of the book series: Methods and Tools in Biosciences and Medicine ((MTBM))

Abstract

In prion disease, accumulation of PrPSc and PrP amyloid in the central nervous system (CNS) is accompanied by activation of microglial cells, hypertrophy and proliferation of astrocytes, and degeneration of neurons, leading to variable degrees of atrophy of the target regions. The temporal and anatomical correlation between PrPSc deposition and the development of neuropathological changes suggests that altered forms of the protein are responsible for the nerve cell degeneration and glial cell reaction [1-5]. In principle, one could directly test the toxic effect of PrPSc by applying the purified protein to neurons in culture. Although there have been several reports of such experiments [6-8], they are difficult to interpret because of uncertainties about the physical state of the PrPSc, since detergents needed to keep the protein in solution have to be removed before it can be applied to cell cultures. An alternative strategy is to analyze the effect on cultured neurons of synthetic peptides derived from the PrP sequence.

This is a preview of subscription content, 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   39.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   239.00
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

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Reference

Further reading

  • Caughey B (ed) (2001) Prion proteins. In: FM Richards, DS Eisenberg (eds): Advances in Protein Chemistry. Volume 57. Academic Press, San Diego.

    Google Scholar 

  • Wetzel R (ed) (1999) Methods in Enzymology, Volume 309: Amyloids,Prions and Other Protein Aggregates. Academic Press, San Diego

    Google Scholar 

  • Anonymous (1992) Special issue: Is beta-amyloid neurotoxic? Neurobiol Aging 13: 535–625

    Article  Google Scholar 

  • Chiti F, Stefani M, Taddei N et al. (2003) Rationalization of the effects of mutations on peptide and protein aggregation rates. Nature 424: 805–808

    Article  PubMed  CAS  Google Scholar 

Reference

  1. DeArmond SJ, Mobley WC, DeMott DL et al. (1998) Changes in the localization of brain prion proteins during scrapie infection. Neurology 50: 1271–1280

    PubMed  CAS  Google Scholar 

  2. Jendroska K, Heinzel FP, Torchia M et al. (1991) Proteinase-resistant prion protein accumulation in Syrian hamster brain correlates with regional pathology and scrapie infectivity. Neurology 41: 8 1482–1490

    Article  PubMed  CAS  Google Scholar 

  3. Williams A, Lucassen PJ, Ritchie D, Bruce M (1997) PrP deposition, microglial activation, and neuronal apoptosis in marine scrapie. Exp Neurol 144: 433–9 438

    Article  PubMed  CAS  Google Scholar 

  4. Bruce ME, McBride PA, Farquhar CF (1989) Precise targeting of the pathology of the sialoglycoprotein, PrP, and vacuo- 10 lar degeneration in mouse scrapie. Neurosci Lett 102: 1–6

    Article  PubMed  CAS  Google Scholar 

  5. Jeffrey M, Martin S, Barr J et al. (2001) Onset of accumulation of PrP’ in murine Me7 scrapie in relation to pathological and PrP immunohistochemic al changes. J Comp Pathol 124: 20–28

    Article  PubMed  CAS  Google Scholar 

  6. Muller WE, Ushijima H, Schroder HC et al. (1993) Cytoprotective effect of NMDA receptor antagonists on prion protein (prionSc)-induced toxicity in rat cortical cell cultures. Eur J Pharmacol 246: 261–267

    Article  PubMed  CAS  Google Scholar 

  7. Giese A, Brown DR, Groschup MH et al. (1998) Role of microglia in neuronal cell death in prion disease. Brain Pathol 8: 449–457

    Article  PubMed  CAS  Google Scholar 

  8. Post K, Brown DR, Groschup M et al. (2000) Neurotoxicity but not infectivity of prion proteins can be induced reversibly in vitro. Arch Virol Suppl 16: 265–273

    PubMed  Google Scholar 

  9. Tagliavini F, Forloni G, D’Ursi P et al. (2001) Studies on peptide fragments of prion proteins. Adv Protein Chem 57: 171–201

    Article  PubMed  CAS  Google Scholar 

  10. Selvaggini C, De Gioia L, Cantu L et al. (1993) Molecular characteristics of a protease-resistant, amyloidogenic and neurotoxic peptide homologous to residues 106–126 of the prion protein. Biochem Biophys Res Commun 194: 1380–386

    Article  PubMed  CAS  Google Scholar 

  11. De Gioia L, Selvaggini C, Ghibaudi E et al. (1994) Conformational polymorphism of the amyloidogenic and neurotoxic pep-tide homologous to residues 106–126 of the prion protein J Biol Chem 269: 7859–7862

    PubMed  Google Scholar 

  12. Forloni G, Angeretti N, Chiesa R et al. (1993) Neurotoxicity of a prion protein fragment. Nature 362: 543–546

    Article  PubMed  CAS  Google Scholar 

  13. Forloni G, Del Bo R, Angeretti N et al. (1994) A neurotoxic prion protein fragment induces rat astroglial proliferation and hypertrophy. Eur J Neurosci 6: 1415–1422

    Article  PubMed  CAS  Google Scholar 

  14. Salmona M, Forloni G, Diomede L et al. (1997) A neurotoxic and gliotrophic fragment of the prion protein increases plasma membrane microviscosity. Neurobiol Dis 4: 47–57

    Article  PubMed  CAS  Google Scholar 

  15. Tagliavini F, Prelli F, Ghiso J et al. (1991) Amyloid protein of Gerstmann-Sträussler-Scheinker disease (Indiana kindred) is an 11 kd fragment of prion protein with an N-terminal glycine at codon 58. EMBO J 10: 513–519

    PubMed  CAS  Google Scholar 

  16. Tagliavini F, Prelli F, Porro Metal. (1994) Amyloid fibrils in Gerstmann-StrausslerScheinker disease (Indiana and Swedish kindreds) express only PrP peptides encoded by the mutant allele. Cell 79: 695–703

    Article  PubMed  CAS  Google Scholar 

  17. Chen SG, Teplow DB, Parchi P et al. (1995) Truncated forms of the human prion protein in normal brain and in prion diseases. J Biol Chem 270: 19173–19180

    Article  PubMed  CAS  Google Scholar 

  18. Parchi P, Castellani R, Capellari S et al. (1996) Molecular basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease. Ann Neurol 39: 767–778

    Article  PubMed  CAS  Google Scholar 

  19. Piccardo P, Seiler C, Dlouhy SR et al. (1996) Proteinase-k-resistant prion protein isoforms in Gerstmann-Sträussler-Scheinker disease (Indiana kindred). J Neuropathol Exp Neurol 55: 1157–1163

    Article  PubMed  CAS  Google Scholar 

  20. Brown DR, Herms J, Kretzschmar HA (1994) Mouse cortical cells lacking cellular PrP survive in culture with a neurotoxic PrP fragment. Neuroreport 5: 2057–2060

    Article  PubMed  CAS  Google Scholar 

  21. Brown DR, Schmidt B, Kretzschmar HA (1996) Role of microglia and host prion protein in neurotoxicity of a prion protein fragment. Nature 380: 345–347

    Article  PubMed  CAS  Google Scholar 

  22. Haik S, Peyrin JM, Lins L et al. (2000) Neurotoxicity of the putative transmembrane domain of the prion protein. Neurobiol Dis 7: 644–656

    Article  PubMed  CAS  Google Scholar 

  23. Chabry J, Ratsimanohatra C, Sponne I et al. (2003) In vivo and in vitro neurotoxicity of the human prion protein (PrP) fragment p118–135 independently of PrP expression. J Neurosci 23: 462–469

    PubMed  CAS  Google Scholar 

  24. Tagliavini F, Forloni G, Colombo L et al. (2000) Tetracycline affects abnormal properties of synthetic PrP peptides and PrPs’ in vitro. J Mol Biol 300: 1309–1322

    Article  CAS  Google Scholar 

  25. Bonetto V, Massignan T, Chiesa R et al. (2002) Synthetic miniprion PrP106. J Biol Chem 277: 31327–31334

    Article  PubMed  CAS  Google Scholar 

  26. Salmona M, Morbin M, Massignan T et al. (2003) Structural properties of Gerstmann-Sträussler-Scheinker disease amyloid protein. J Biol Chem 278: 48146–48153

    Article  PubMed  CAS  Google Scholar 

  27. Salmona M, Malesani P, De Gioia L et al. (1999) Molecular determinants of the physicochemical properties of a critical prion protein region comprising residues 106–126. Biochem J 342 (Pt 1): 207–214

    Article  PubMed  CAS  Google Scholar 

  28. Kunz B, Sandmeier E, Christen P (1999) Neurotoxicity of prion peptide 106–126 not confirmed. FEBS Lett 458: 65–68

    Article  PubMed  CAS  Google Scholar 

  29. Brown DR (1999) Comment on: Neurotoxicity of prion peptide 106–126 not confirmed by Beat Kunz, Erika Sandmeier, Philipp Christen. FEBS Lett 460: 559–560

    Article  PubMed  CAS  Google Scholar 

  30. Forloni G, Salmona M, Bugiani O, Tagliavini F (2000) Comment on: Neurotoxicity of prion peptide 106–126 not confirmed by Beat Kunz, Erika Sandmeier, Philipp Christen. FEBS Lett 466: 205–206

    Article  PubMed  CAS  Google Scholar 

  31. Ball HL, Mascagni P (1992) Purification of synthetic peptides using reversible chromatographic probes based on the Fmoc molecule. Int J Pept Protein Res 40: 370–379

    Article  PubMed  CAS  Google Scholar 

  32. Sarin VK, Kent SB, Tam JP, Merrifield RB (1981) Quantitative monitoring of solid-phase peptide synthesis by the ninhydrin reaction. Anal Biochem 117: 147–157

    Article  PubMed  CAS  Google Scholar 

  33. Kyte J, Doolittle RF (1982) A simple method for displaying the hydropathic character of a protein. J Mol Biol 157: 105–132

    Article  PubMed  CAS  Google Scholar 

  34. Deleage G, Roux B (1987) An algorithm for protein secondary structure prediction based on class prediction. Protein Eng 1: 289–294

    Article  CAS  Google Scholar 

  35. Krogh A, Larsson B, von Heijne G, Sonnhammer EL (2001) Predicting trans-membrane protein topology with a hidden Markov model: Application to complete genomes. J Mol Biol 305: 567–580

    Article  PubMed  CAS  Google Scholar 

  36. Sreerama N, Woody RW (2000) Estimation of protein secondary structure from circular dichroism spectra: Comparison of contin, selcon, and cdsstr methods with an expanded reference set. Anal Biochem 287: 252–260

    Article  PubMed  CAS  Google Scholar 

  37. Shahar A, de Vellis J, Vernadakis A, Haber B (eds) (1989) A dissection and tissue culture manual of the nervous system, Alan R. Liss, Inc., New York

    Google Scholar 

  38. Liu Y, Peterson DA, Kimura H, Schubert D (1997) Mechanism of cellular 344,5- dimethylthiazol-2-y1)-2,5-cliphenyltetrazolium bromide (MTT) reduction. J Neurochem 69: 581–593

    Article  PubMed  CAS  Google Scholar 

  39. Chiesa R, Angeretti N, Lucca E et al. (1996) Clusterin (Sgp-2) induction in rat astroglial cells exposed to prion protein fragment 106–126. Eur J Neurosci 8: 589–597

    Article  PubMed  CAS  Google Scholar 

  40. Hartley DM, Walsh DM, Ye CP et al. (1999) Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons. J Neurosci 19: 8876–8884

    PubMed  CAS  Google Scholar 

  41. Walsh DM, Klyubin I, Fadeeva JV et al. (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416: 535–539

    Article  CAS  Google Scholar 

  42. Bucciantini M, Giannoni E, Chiti F et al. (2002) Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature 416: 507–511

    Article  PubMed  CAS  Google Scholar 

  43. Kayed R, Head E, Thompson JL et al. (2003) Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300: 486–489

    Article  PubMed  CAS  Google Scholar 

  44. Soto C, Castano EM, Kumar RA et al. (1995) Fibrillogenesis of synthetic amyloid-beta peptides is dependent on their initial secondary structure. Neurosci Lett 200: 105–158

    Article  PubMed  CAS  Google Scholar 

  45. Telling GC, Scott M, Mastrianni J et al. (1995) Prion propagation in mice expressing human and chimeric PrP trans-genes implicates the interaction of cellular PrP with another protein. Cell 83: 79–90

    Article  PubMed  CAS  Google Scholar 

  46. Forloni G, Angeretti N, Malesani P et al. (1999) Influence of mutations associated with familial prion-related encephalopathies on biological activity of prion protein peptides. Ann Neurol 45: 489–494

    Article  PubMed  CAS  Google Scholar 

  47. Barret A, Tagliavini F, Forloni G et al. (2003) Evaluation of quinacrine treatment for prion diseases. J Virol 77: 8462–8469

    Article  PubMed  CAS  Google Scholar 

  48. Forloni G, Bugiani O, Tagliavini F, Salmona M (1996) Apoptosis-mediated neurotoxicity induced by beta-amyloid and PrP fragments. Mol Chem Neuropathol 28: 163–171

    Article  PubMed  CAS  Google Scholar 

  49. Chiesa R, Piccardo P, Quaglio E et al. (2003) Molecular distinction between pathogenic and infectious properties of the prion protein. J Virol 77: 7611–7622

    Article  PubMed  CAS  Google Scholar 

  50. Tagliavini F, McArthur RA, Canciani B et al. (1997) Effectiveness of anthracycline against experimental prion disease in Syrian hamsters. Science 276: 1119–1122

    Article  PubMed  CAS  Google Scholar 

  51. Forloni G, Iussich S, Awan T et al. (2002) Tetracyclines affect prion infectivity. Proc Natl Acad Sci USA 99: 10849–10854

    Article  PubMed  CAS  Google Scholar 

  52. Harris DA (1999) Cellular biology of prion diseases. Clin Microbiol Rev 12: 429–444

    PubMed  CAS  Google Scholar 

  53. Hegde RS, Tremblay P, Groth D et al. (1999) Transmissible and genetic prion diseases share a common pathway of neurodegeneration. Nature 402: 822–826

    Article  PubMed  CAS  Google Scholar 

  54. Kourie JI (2001) Mechanisms of prioninduced modifications in membrane transport properties: Implications for signal transduction and neurotoxicity. Chem Biol Interact 138: 1–26

    Article  PubMed  CAS  Google Scholar 

  55. Bahadi R, Farrelly PV, Kenna BL et al. (2003) Channels formed with a mutant prion protein PrP(82–146) homologous to a 7-kda fragment in diseased brain of GSS patients. Am J Physiol Cell Physiol 285: C862–872

    PubMed  CAS  Google Scholar 

  56. Brown DR, Kretzschmar HA (1997) Microglia and prion disease: A review. Histol Histopathol 12: 883–892

    PubMed  CAS  Google Scholar 

  57. Hope J, Shearman MS, Baxter HC et al. (1996) Cytotoxicity of prion protein peptide (PrP106–126) differs in mechanism from the cytotoxic activity of the Alzheimer’s disease amyloid peptide, a-beta25–35. Neurodegeneration 5: 1–11

    Article  PubMed  CAS  Google Scholar 

  58. Deli MA, Sakaguchi S, Nakaoke R et al. (2000) PrP fragment 106–126 is toxic to cerebral endothelial cells expressing PrPc. Neuroreport 11: 3931–3936

    Article  PubMed  CAS  Google Scholar 

  59. O’Donovan CN, Tobin D, Cotter TG (2001) Prion protein fragment PrP(106–126) induces apoptosis via mitochondrial disruption in human neuronal SH-SY5Y cells. J Biol Chem 276: 43516–43523

    Article  PubMed  Google Scholar 

  60. Hanan E, Goren O, Eshkenazy M, Solomon B (2001) Immunomodulation of the human prion peptide 106–126 aggregation. Biochem Biophys Res Commun 280: 115–120

    Article  PubMed  CAS  Google Scholar 

  61. Della-Bianca V, Rossi F, Armato U et al. (2001) Neurotrophin p75 receptor is involved in neuronal damage by prion peptide-(106–126). J Biol Chem 276: 38929–38933

    Article  PubMed  CAS  Google Scholar 

  62. Thellung S, Villa V, Corsaro A et al. (2002) P38 MAP kinase mediates the cell death induced by PrP106–126 in the SH-SY5Y neuroblastoma cells. Neurobiol Dis 9: 69–81

    Article  PubMed  CAS  Google Scholar 

  63. Jobling MF, Stewart LR, White AR et al. (1999) The hydrophobic core sequence modulates the neurotoxic and secondary structure properties of the prion peptide 106–126. J Neurochem 73: 1557–1565

    Article  PubMed  CAS  Google Scholar 

  64. Fioriti L, Quaglio E, Massignan T et al. (2004) The neurotoxicity of prion protein (PrP) peptide 106–126 is independent of the expression level of PrP an is not medicated by abnormal PrP species. Mol Cell Neurosci; in press

    Google Scholar 

  65. Hegde RS, Mastrianni JA, Scott MR et al. (1998) A transmembrane form of the prion protein in neurodegenerative disease. Science 279: 827–834

    Article  PubMed  CAS  Google Scholar 

  66. Ma J, Wollmann R, Lindquist S (2002) Neurotoxicity and neurodegeneration when PrP accumulates in the cytosol. Science 17: 17

    Google Scholar 

  67. Chiesa R, Harris DA (2001) Prion diseases: What is the neurotoxic molecule? Neurobiol Dis 8: 743–763

    Article  PubMed  CAS  Google Scholar 

Download references

Authors
  1. Roberto Chiesa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luana Fioriti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fabrizio Tagliavini
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mario Salmona
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gianluigi Forloni
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Institut de Génétique Humaine, CNRS U.P.R. 1142, 141, rue de la Cardonille, Montpellier Cedex 5, F-34396, France

    Sylvain Lehmann

  2. Service de Pharmacologie et d’Immunologie, Bâtiment 136, CEA/Saclay, Gif sur Yvette Cedex, F-91191, France

    Jacques Grassi

Rights and permissions

Reprints and permissions

Copyright information

© 2004 Springer Basel AG

About this chapter

Cite this chapter

Chiesa, R., Fioriti, L., Tagliavini, F., Salmona, M., Forloni, G. (2004). Cytotoxicity of PrP Peptides. In: Lehmann, S., Grassi, J. (eds) Techniques in Prion Research. Methods and Tools in Biosciences and Medicine. Birkhäuser, Basel. https://doi.org/10.1007/978-3-0348-7949-1_13

Download citation

  • DOI: https://doi.org/10.1007/978-3-0348-7949-1_13

  • Publisher Name: Birkhäuser, Basel

  • Print ISBN: 978-3-7643-2224-3

  • Online ISBN: 978-3-0348-7949-1

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation