Skip to main content

Central Pathogenesis of Prion Diseases

  • Chapter
Neurodegeneration and Prion Disease

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
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

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. C. Cunningham, R. Deacon, H. Wells, D. Boche, S. Waters, C. Picanco Diniz, H. Scott, J. N. P. Rawlins, and V. H. Perry, Synaptic changes characterize early behavioural signs in the ME7 model of murine prion disease. Eur. J. Neurosci. 17, 2147–2155 (2003).

    Article  PubMed  Google Scholar 

  2. S. Brandner, S. Isenmann, A. Raeber, M. Fischer, A. Sailer, Y. Kobayashi, S. Marino, C. Weissmann, and A. Aguzzi, Normal host prion protein necessary for scrapie-induced neurotoxicity. Nature 379, 339–343 (1996).

    Article  PubMed  Google Scholar 

  3. G. Mallucci, A. Dickinson, J. Linehan, R-C. Klöhn, S. Brandner, and J. Collinge, Depleting neuronal PrP in prion infection prevents disease and reverses spongiosis. Science 302, 871–874 (2003).

    Article  PubMed  Google Scholar 

  4. H. Büeler, A. Aguzzi, A. Sailer, R.-A. Greiner, P. Autenried, M. Aguet, and C. Weissmann, Mice devoid of PrP are resistant to scrapie. Cell 73, 1339–1347 (1993).

    Article  PubMed  Google Scholar 

  5. J. C. Manson, A. R. Clarke, R A. McBride, I. McConnell, and J. Hope, PrP gene dosage determines the timing but not the final intensity or distribution of lesions in scrapie pathology. Neurodegeneration 3, 331–340 (1994).

    PubMed  Google Scholar 

  6. R. E. Race, S. A. Priola, R. A. Bessen, D. Ernst, J. Dockter, G. F. Rall, L. Mucke, B. Chesebro, and M. B. Oldstone, Neuron-specific expression of a hamster prion protein minigene in transgenic mice induces susceptibility to hamster scrapie agent. Neuron 15, 1183–1191 (1995).

    PubMed  Google Scholar 

  7. A. J. Raeber, R. E. Race, S. Brandner, S. A. Priola, A. Sailer, R. A. Bessen, L. Mucke, J. Manson, A. Aguzzi, M. B. A. Oldstone, C. Weissmann, and B. Chesebro, Astrocyte-specific expression of hamster prion protein (PrP) renders PrP knockout mice susceptible to hamster scrapie. EMBO J. 16, 6057–6065 (1997).

    PubMed  Google Scholar 

  8. M. Prinz, F. Montrasio, H. Furukawa, M. E. van der Haar, P. Schwarz, T. Rülicke, O. T. Giger, K.-G. Häusler, D. Perez, M. Glatzel, and A. Aguzzi, Intrinsic resistance of oligodendrocytes to prion infection. J. Neurosci. 24, 5974–5981 (2004).

    PubMed  Google Scholar 

  9. M. Jeffrey, C. M. Goodsir, R. E. Race, and B. Chesebro, Scrapie-specific neuronal lesions are independent of neuronal PrP expression. Ann. Neurol. 55, 781–792 (2004).

    PubMed  Google Scholar 

  10. H. Büeler, M. Fischer, Y. Lang, H. Bluethmann, H.-P. Lipp, S. J. DeArmond, S. B. Prusiner, M. Aguet, and C. Weissmann, Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature 356, 577–582 (1992).

    Article  PubMed  Google Scholar 

  11. J. C. Manson, A. R. Clarke, M. L. Hooper, L. Aitchison, I. McConnell, and J. Hope, 129/Ola mice carrying a null mutation in PrP that abolishes mRNA production are developmentally normal. Mol. Neurobiol. 8, 121–127 (1994).

    PubMed  Google Scholar 

  12. J. Collinge, M. A. Whittington, K. C. L. Sidle, C. J. Smith, M. S. Palmer, A. R. Clarke, and J. G. R. Jefferys, Prion protein is necessary for normal synaptic function. Nature 370, 295–297 (1994).

    PubMed  Google Scholar 

  13. I. Tobler, S. E. Gaus, T Deboer, P. Achermann, M. Fischer, T. Rülicke, M. Moser, B. Oesch, R A. McBride, and J. C. Manson, Altered circadian activity rhythms and sleep in mice devoid of prion protein. Nature 380, 639–642 (1996).

    PubMed  Google Scholar 

  14. G. R. Mallucci, S. Ratté, E. A. Asante, J. Linehan, I. Gowland, J. G. R. Jefferys, and J. Collinge, Post-natal knockout of prion protein alters hippocampal CA1 properties, but does not result in neurodegeneration. EMBO J. 21, 202–210 (2002).

    PubMed  Google Scholar 

  15. D. R. Brown, R. S. J. Nicholas, and L. Canevari, Lack of prion protein expression results in a neuronal phenotype sensitive to stress. J. Neurosci. Res. 67, 211–224 (2002).

    PubMed  Google Scholar 

  16. S. Sakaguchi, S. Katamine, N. Nishida, R. Moriuchi, K. Shigematsu, T. Sugimoto, A. Nakatani, Y. Kataoka, T. Houtani, S. Shirabe, H. Okada, S. Hasegawa, T. Miyamoto, and T Noda, Loss of cerebellar Purkinje cells in aged mice homozygous for a disrupted PrP gene. Nature 380, 528–531 (1996).

    PubMed  Google Scholar 

  17. D. Rossi, A. Cozzio, E. Flechsig, M. A. Klein, T. Rülicke, A. Aguzzi, and C. Weissmann, Onset of ataxia and Purkinje cell loss in PrP null mice inversely correlated with Dpl level in brain. EMBO J. 20, 694–702 (2001).

    PubMed  Google Scholar 

  18. R. C. Moore, I. Y. Lee, G. L. Silverman, R M. Harrison, R. Strome, C. Heinrich, A. Karunaratne, S. H. Pasternak, M. A. Chishti, Y. Liang, P. Mastrangelo, K. Wang, A. F. Smit, S. Katamine, G. A. Carlson, F E. Cohen, S. B. Prusiner, D. W. Melton, P. Tremblay, L. E. Hood, and D. Westaway, Ataxia in prion protein (PrP)-deficient mice is associated with upregulation of the novel PrP-like protein doppel. J. Mol. Biol. 292, 797–817 (1999).

    PubMed  Google Scholar 

  19. H. Budka, Histopathology and immunohistochemistry of human transmissible spongiform encephalopathies (TSEs). Arch. Virol. [Suppl.] 16, 135–142 (2000).

    Google Scholar 

  20. H. Budka, Neuropathology of prion diseases. Br. Med. Bull. 66, 121–130 (2003).

    PubMed  Google Scholar 

  21. P. Parchi, A. Giese, S. Capellari, P. Brown, W. Schulz-Schaeffer, O. Windl, I. Zerr, H. Budka, N. Kopp, P. Piccardo, S. Poser, A. Rojiani, N. Streichemberger, J. Julien, C. Vital, B. Ghetti, P. Gambetti, and H. Kretzschmar, Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann. Neurol. 46, 224–233 (1999).

    PubMed  Google Scholar 

  22. A. F. Hill, S. Joiner, J. D. F Wadsworth, K. C. L. Sidle, J. E. Bell, H. Budka, J. W. Ironside, and J. Collinge, Molecular classification of sporadic Creutzfeldt-Jakob disease. Brain 126, 1333–1346 (2003).

    PubMed  Google Scholar 

  23. G. Almer, J. A. Hainfellner, T. Brücke, K. Jellinger, R. Kleinert, G. Bayer, O. Windl, H. A. Kretzschmar, A. Hill, K. Sidle, J. Collinge, and H. Budka, Fatal familial insomnia: a new Austrian family. Brain 122, 5–16 (1999).

    PubMed  Google Scholar 

  24. H. Büeler, A. Raeber, A. Sailer, M. Fischer, A. Aguzzi, and C. Weissmann, High prion and PrPSc levels but delayed onset of disease in scrapie-inoculated mice heterozygous for a disrupted PrP gene. Mol. Med. 1, 19–30 (1994).

    PubMed  Google Scholar 

  25. H. A. Kretzschmar, S. B. Prusiner, L. E. Stowring, and S. J. DeArmond, Scrapie prion proteins are synthesized in neurons. Am. J. Pathol. 122, 1–5 (1986).

    PubMed  Google Scholar 

  26. A. Giese and H. A. Kretzschmar, Prion-induced neuronal damage—the mechanisms of neuronal destruction in the subacute spongiform encephalopathies. Curr. Top. Microbiol. Immunol. 253, 203–217 (2001).

    PubMed  Google Scholar 

  27. M. Guentchev, J.-A. Hainfellner, G. R. Trabattoni, and H. Budka, Distribution of parvalbumin-immunoreactive neurons in brain correlates with hippocampal and temporal cortical pathology in Creutzfeldt-Jakob disease. J. Neuropathol. Exp. Neurol. 56, 1119–1124 (1997).

    PubMed  Google Scholar 

  28. R. V. Belichenko, J. Miklossy, B. Belser, H. Budka, and M. R. Celio, Early destruction of the extracellular matrix around parvalbumin-immunoreactive interneurons in Creutzfeldt-Jakob disease. Neurobiol. Dis. 6, 269–279 (1999).

    PubMed  Google Scholar 

  29. M. Guentchev, M. H. Groschup, R. Kordek, P. P. Liberski, and H. Budka, Severe, early and selective loss of a subpopulation of GABAergic inhibitory neurons in experimental transmissible spongiform encephalopathies. Brain Pathol. 8, 615–623 (1998).

    PubMed  Google Scholar 

  30. M. Guentchev, J. Wanschitz, T Voigtländer, H. Flicker, and H. Budka, Selective neuronal vulnerability in human prion diseases. Fatal familial insomnia differs from other types of prion diseases. Am. J. Pathol. 155, 1453–1457 (1999).

    PubMed  Google Scholar 

  31. T. Arendt, V Bigl, and A. Arendt, Neurone loss in the nucleus basalis of Meynert in Creutzfeldt-Jakob disease. Acta Neuropathol. 65, 85–88 (1984).

    PubMed  Google Scholar 

  32. L. Cartier, R. Verdugo, C. Vergara, and S. Galvez, The nucleus basalis of Meynert in 20 definite cases of Creutzfeldt-Jakob disease. J. Neurol. Neurosurg. Psychiatry 52, 304–309 (1989).

    PubMed  Google Scholar 

  33. M. E. Bruce, TSE strain variation. Br. Med. Bull. 66, 99–108 (2003).

    PubMed  Google Scholar 

  34. M. E. Bruce, I. McConnell, H. Fraser, and A. G. Dickinson, The disease characteristics of different strains of scrapie in Sinc congenic mouse lines: implications for the nature of the agent and host control of pathogenesis. J. Gen. Virol. 72, 595–603 (1991).

    PubMed  Google Scholar 

  35. H. Fraser, Diversity in the neuropathology of scrapie-like diseases in animals. Br. Med. Bull. 49, 792–809 (1993).

    PubMed  Google Scholar 

  36. S. J. DeArmond, W. C. Mobley, D. L. DeMott, R. A. Barry, J. H. Beckstead, and S. B. Prusiner, Changes in the localization of brain prion proteins during scrapie infection. Neurology 37, 1271–1280 (1987).

    PubMed  Google Scholar 

  37. K. Jendroska, F. P. Heinzel, M. Torchia, L. Stowring, H. A. Kretzschmar, A. Kon, A. Stern, S. B. Prusiner, and S. J. DeArmond, Proteinase-resistant prion protein accumulation in Syrian hamster brain correlates with regional pathology and scrapie infectivity. Neurology 41, 1482–1490 (1991).

    PubMed  Google Scholar 

  38. R. Kordek, J. A. Hainfellner, P. P. Liberski, and H. Budka, Deposition of the prion protein (PrP) during the evolution of experimental Creutzfeldt-Jakob disease. Acta Neuropathol. 98, 597–602 (1999).

    PubMed  Google Scholar 

  39. A. Dorandeu, L. Wingertsmann, F. Chrétien, M.-B. Delisle, C. Vital, P. Parchi, P. Montagna, E. Lugaresi, J. W. Ironside, H. Budka, P. Gambetti, and F. Gray, Neuronal apoptosis in fatal familial insomnia. Brain Pathol. 8, 531–537 (1998).

    PubMed  Google Scholar 

  40. R. S. Hegde, J. A. Mastrianni, M. R. Scott, K. A. DeFea, P. Tremblay, M. Torchia, S. J. DeArmond, S. B. Prusiner, and V. R. Lingappa, A transmembrane form of the prion protein in neurodegenerative disease. Science 279, 827–834 (1998).

    PubMed  Google Scholar 

  41. G. Forloni, N. Angeretti, R. Chiesa, E. Monzani, M. Salmona, O. Bugiani, and F. Tagliavini, Neurotoxicity of a prion protein fragment. Nature 362, 543–546 (1993).

    Article  PubMed  Google Scholar 

  42. L. De Gioia, C. Selvaggini, E. Ghibaudi, L. Diomede, O. Bugiani, G. Forloni, F. Tagliavini, and M. Salmona, Conformational polymorphism of the amyloidogenic and neurotoxic peptide homologous to residues 106–126 of the prion protein. J. Biol. Chem. 269, 7859–7862 (1994).

    PubMed  Google Scholar 

  43. C. Selvaggini, L. De Gioia, L. Cantu, E. Ghibaudi, L. Diomede, F. Passerini, G. Forloni, O. Bugiani, F. Tagliavini, and M. Salmona, Molecular characteristics of a protease-resistant, amyloidogenicand neurotoxic peptide homologous to residues 106–126 of the prion protein. Biochem. Biophys. Res. Commun. 194, 1380–1386 (1993).

    PubMed  Google Scholar 

  44. M. F. Jobling, L. R. Stewart, A. R. White, C. McLean, A. Friedhuber, F. Maher, K. Beyreuther, C. L. Masters, C. J. Barrow, S. J. Collins, and R. Cappai, The hydrophobic core sequence modulates the neurotoxic and secondary structure properties of the prion peptide 106–126. J. Neurochem. 73, 1557–1565 (1999).

    PubMed  Google Scholar 

  45. M. F. Jobling, X. Huang, L. R. Stewart, K. J. Barnham, C. Curtain, I. Volitakis, M. Perugini, A. R. White, R. A. Cherny, C. L Masters, C. J. Barrow, S. J. Collins, A. I. Bush, and R. Cappai, Copper and zinc binding modulates the aggregation and neurotoxic properties of the prion peptide PrP106–126. Biochemistry 40, 8073–8084 (2001).

    PubMed  Google Scholar 

  46. D. R. Brown, J. Herms, and H. A. Kretzschmar, Mouse cortical cells lacking cellular PrP survive in culture with a neurotoxic PrP fragment. Neuroreport 5, 2057–2060 (1994).

    PubMed  Google Scholar 

  47. D. R. Brown, Prion protein-overexpressing cells show altered response to a neurotoxic prion protein peptide. J. Neurosci. Res. 54, 331–340 (1998).

    PubMed  Google Scholar 

  48. D. R. Brown, B. Schmidt, and H. A. Kretzschmar, Role of microglia and host prion protein in neurotoxicity of a prion protein fragment. Nature 380, 345–347 (1996).

    PubMed  Google Scholar 

  49. D. R. Brown, Prion protein peptide neurotoxicity can be mediated by astrocytes. J. Neurochem. 73, 1105–1113 (1999).

    PubMed  Google Scholar 

  50. W. E. Muller, H. Ushijima, H. C. Schroder, J. M. Forrest, W. F. Schatton, P. G. Rytik, and M. Heffner-Lauc, Cytoprotective effect of NMDA receptor antagonists on prion protein (PrionSc)-induced toxicity in rat cortical cell cultures. Eur. J. Pharmacol. 246, 261–267 (1993).

    PubMed  Google Scholar 

  51. D. R. Brown, J. W. Herms, B. Schmidt, and H. A. Kretzschmar, PrP and beta-amyloid fragments activate different neurotoxic mechanisms in cultured mouse cells. Eur. J. Neurosci. 9, 1162–1169 (1997).

    PubMed  Google Scholar 

  52. L. R. Stewart, A. R. White, M. F. Jobling, B. E. Needham, F. Maher, J. Thyer, K. Beyreuther, C. L. Masters, S. J. Collins, and R. Cappai, Involvement of the 5-lipoxygenase pathway in the neurotoxicity of the prion peptide PrP106–126. J. Neurosci. Res. 65, 565–572 (2001).

    PubMed  Google Scholar 

  53. T. van Rheede, M. M. W. Smolenaars, O. Madsen, and W. W. de Jong, Molecular evolution of the mammalian prion protein. Mol. Biol. Evol. 20, 111–121 (2003).

    PubMed  Google Scholar 

  54. M. P. Hornshaw, J. R. McDermott, and J. M. Candy, Copper binding to the N-terminal tandem repeat regions of mammalian and avian prion protein. Biochem. Biophys. Res. Commun. 207, 621–629 (1995).

    PubMed  Google Scholar 

  55. M. P. Hornshaw, J. R. McDermott, J. M. Candy, and J. H. Lakey, Copper binding to the N-terminal tandem repeat region of mammalian and avian prion protein: structural studies using synthetic peptides. Biochem. Biophys. Res. Commun. 214, 993–999 (1995).

    PubMed  Google Scholar 

  56. T. Miura, A. Hori-i, and H. Takeuchi, Metal-dependent alpha-helix formation promoted by the glycine-rich octapeptide region of prion protein. FEBS Lett. 396, 248–252 (1996).

    PubMed  Google Scholar 

  57. P. C. Pauly and D. A. Harris, Copper stimulates endocytosis of the prion protein. J. Biol. Chem. 273, 33107–33110 (1998).

    PubMed  Google Scholar 

  58. D. R. Brown, K. Qin, J. W. Herms, A. Madlung, J. Manson, R. Strome, P. E. Fraser, T. Kruck, A. von Bohlen, W. Schulz-Schaeffer, A. Giese, D. Westaway, and H. Kretzschmar, The cellular prion protein binds copper in vivo. Nature 390, 684–687 (1997).

    PubMed  Google Scholar 

  59. J. H. Viles, F. E. Cohen, S. B. Prusiner, D. B. Goodin, R E. Wright, and H. J. Dyson, Copper binding to the prion protein: structural implications of four identical cooperative binding sites. Proc. Natl. Acad. Sci. USA 96, 2042–2047 (1999).

    PubMed  Google Scholar 

  60. M. L. Kramer, H. D. Kratzin, B. Schmidt, A. Römer, O. Windl, S. Liemann, S. Hornemann, and H. Kretzschmar, Prion protein binds copper within the physiological concentration range. J. Biol. Chem. 276, 16711–16719 (2001).

    PubMed  Google Scholar 

  61. J. Stöckel, J. Safar, A. C. Wallace, F E. Cohen, and S. B. Prusiner, Prion protein selectively binds copper(II) ions. Biochemistry 37, 7185–7193 (1998).

    PubMed  Google Scholar 

  62. K. Qin, D.-S. Yang, Y. Yang, M. A. Chishti, L.-J. Meng, H. A. Kretzschmar, C. M. Yip, P. E. Fraser, and D. Westaway, Copper(ll)-induced conformational changes and protease resistance in recombinant and cellular PrP. Effect of protein age and deamidation. J. Biol. Chem. 275, 19121–19131 (2000).

    PubMed  Google Scholar 

  63. E. Quaglio, R. Chiesa, and D. A. Harris, Copper converts the cellular prion protein into a protease-resistant species that is distinct from the scrapie isoform. J. Biol. Chem. 276, 11432–11438 (2001).

    PubMed  Google Scholar 

  64. D. R. Brown, B. Schmidt, and H. A. Kretzschmar, Effects of oxidative stress on prion protein expression in PC12 cells. Int. J. Dev. Neurosci. 15, 961–972 (1997).

    PubMed  Google Scholar 

  65. D. R. Brown, W. J. Schulz-Schaeffer, B. Schmidt, and H. A. Kretzschmar, Prion protein-deficient cells show altered response to oxidative stress due to decreased SOD-1 activity. Exp. Neurol. 146, 104–112 (1997).

    PubMed  Google Scholar 

  66. W. Rachidi, D. Vilette, P. Guiraud, M. Arlotto, J. Riondel, H. Laude, S. Lehmann, and A. Favier, Expression of prion protein increases cellular copper binding and antioxidant enzyme activities but not copper delivery. J. Biol. Chem. 278, 9064–9072 (2003).

    PubMed  Google Scholar 

  67. A. R. White, S. J. Collins, F. Maher, M. F. Jobling, L. R. Stewart, J. M. Thyer, K. Beyreuther, C. L. Masters, and R. Cappai, Prion protein-deficient neurons reveal lower glutathione reductase activity and increased susceptibility to hydrogen peroxide toxicity. Am. J. Pathol. 155, 1723–1730 (1999).

    PubMed  Google Scholar 

  68. F. Klamt, F. Dal-Pizzol, M. L. Conte da Frota Jr., R. Walz, M. E. Andrades, E. G. da Silva, R. R. Brentani, I. Izquierdo, and J. C. Fonseca Moreira, Imbalance of antioxidant defense in mice lacking cellular prion protein. Free Radic. Biol. Med. 30, 1137–1144 (2001).

    PubMed  Google Scholar 

  69. B.-S. Wong, T. Liu, R. Li, T. Pan, R. B. Petersen, M. A. Smith, P. Gambetti, G. Perry J. C. Manson, D. R. Brown, and M.-S. Sy, Increased levels of oxidative stress markers detected in the brains of mice devoid of prion protein. J. Neurochem. 76, 565–572 (2001).

    PubMed  Google Scholar 

  70. D. R. Brown and A. Besinger, Prion protein expression and superoxide dismutase activity. Biochem. J. 334, 423–429 (1998).

    PubMed  Google Scholar 

  71. D. J. Waggoner, B. Drisaldi, T. B. Bartnikas, R. L. B. Casareno, J. R. Prohaska, J. D. Gitlin, and D. A. Harris, Brain copper content and cuproenzyme activity do not vary with prion protein expression level. J. Biol. Chem. 275, 7455–7458 (2000).

    PubMed  Google Scholar 

  72. D. R. Brown, B.-S. Wong, F. Hafiz, C. Clive, S. J. Haswell, and I. M. Jones, Normal prion protein has an activity like that of superoxide dismutase. Biochem. J. 344, 1–5 (1999).

    PubMed  Google Scholar 

  73. D. R. Brown, C. Clive, and S. J. Haswell, Antioxidant activity related to copper binding of native prion protein. J. Neurochem. 76, 69–76 (2001).

    PubMed  Google Scholar 

  74. B.-S. Wong, T. Pan, T. Liu, R. Li, P. Gambetti, and M.-S. Sy, Differential contribution of superoxide dismutase activity by prion protein in vivo. Biochem. Biophys. Res. Commun. 273, 136–139 (2000).

    PubMed  Google Scholar 

  75. T. Voigtländer, S. Klöppel, P. Birner, C. Jarius, H. Flicker, S. Verghese-Nikolakaki, T. Sklaviadis, M. Guentchev, and H. Budka, Marked increase of neuronal prion protein immunoreactivity in Alzheimer’s disease and human prion diseases. Acta Neuropathol. 101, 417–423 (2001).

    PubMed  Google Scholar 

  76. G. G. Kovacs, P. Zerbi, T. Voigtländer, M. Strohschneider, G. Trabattoni, J. A. Hainfellner, and H. Budka, The prion protein in human neurodegenerative disorders. Neurosci. Lett. 329, 269–272 (2002).

    PubMed  Google Scholar 

  77. D. R. Brown, F. Hafiz, L. L. Glasssmith, B.-S. Wong, I. M. Jones, C. Clive, and S. J. Haswell, Consequences of manganese replacement of copper for prion protein function and proteinase resistance. EMBO J. 19, 1180–1186 (2000).

    PubMed  Google Scholar 

  78. D. R. Brown and J. Sassoon, Copper-dependent functions for the prion protein. Mol. Biotechnol. 22, 165–178 (2002).

    PubMed  Google Scholar 

  79. S. Turnbull, B. J. Tabner, D. R. Brown, and D. Allsop, Copper-dependent generation of hydrogen peroxide from the toxic prion protein fragment PrP106–126. Neurosci. Lett. 336, 159–162 (2003).

    PubMed  Google Scholar 

  80. B.-S. Wong, D. R. Brown, T. Pan, M. Whiteman, T. Liu, X. Bu, R. Li, P. Gambetti, J. Olesik, R. Rubenstein, and M.-S. Sy, Oxidative impairment in scrapie-infected mice is associated with brain metals perturbations and altered antioxidant activities. J. Neurochem. 79, 689–698 (2001).

    PubMed  Google Scholar 

  81. D. W. Lee, H. O. Sohn, H. B. Lim, Y. G. Lee, Y. S. Kim, R. I. Carp, and H. M. Wisniewski, Alteration of free radical metabolism in the brain of mice infected with scrapie agent. Free Radic. Res. 30, 499–507 (1999).

    PubMed  Google Scholar 

  82. H. Ovadia, H. Rosenmann, E. Shezen, M. Halimi, I. Ofran, and R. Gabizon, Effect of scrapie infection on the activity of neuronal nitric-oxide synthase in brain and neuroblastoma cells. J. Biol. Chem. 271, 16856–16861 (1996).

    PubMed  Google Scholar 

  83. G. I. Keshet, H. Ovadia, A. Taraboulos, and R. Gabizon, Scrapie-infected mice and PrP knockout mice share abnormal localization and activity of neuronal nitric oxide synthase. J. Neurochem. 72, 1224–1231 (1999).

    PubMed  Google Scholar 

  84. O. Milhavet, H. E. M. McMahon, W. Rachidi, N. Nishida, S. Katamine, A. Mangé, M. Arlotto, D. Casanova, J. Riondel, A. Favier, and S. Lehmann, Prion infection impairs the cellular response to oxidative stress. Proc. Natl. Acad. Sci. USA 97, 13937–13942 (2000).

    PubMed  Google Scholar 

  85. S.-I. Choi, W.-K. Ju, E.-K. Choi, J. Kim, H.-Z. Lea, R. I. Carp, H. M. Wisniewski, and Y.-S. Kim, Mitochondrial dysfunction induced by oxidative stress in the brains of hamsters infected with the 263 K scrapie agent. Acta Neuropathol. 96, 279–286 (1998).

    PubMed  Google Scholar 

  86. M. Guentchev, T. Voigtländer, C. Haberler, M. H. Groschup, and H. Budka, Evidence for oxidative stress in experimental prion disease. Neurobiol. Dis. 7, 270–273 (2000).

    PubMed  Google Scholar 

  87. Y.-G. Choi, J.-I. Kim, H.-P. Lee, J.-K. Jin, E.-K. Choi, R. I. Carp, and Y.-S. Kim, Induction of heme oxygenase-1 in the brains of scrapie-infected mice. Neurosci. Lett. 289, 173–176 (2000).

    PubMed  Google Scholar 

  88. M. Rizzardini, R. Chiesa, N. Angeretti, E. Lucca, M. Salmona, G. Forloni, and L. Cantoni, Prion protein fragment 106–126 differentially induces heme oxygenase-1 mRNA in cultured neurons and astroglial cells. J. Neurochem. 68, 715–720 (1997).

    PubMed  Google Scholar 

  89. M. Guentchev, S. L. Siedlak, C. Jarius, F. Tagliavini, R. J. Castellani, G. Perry, M. A. Smith, and H. Budka, Oxidative damage to nucleic acids in human prion disease. Neurobiol. Dis. 9, 275–281 (2002).

    PubMed  Google Scholar 

  90. G. G. Kovacs, T. Voigtländer, J. A. Hainfellner, and H. Budka, Distribution of intraneuronal immunoreactivity for the prion protein in human prion diseases. Acta Neuropathol. 104, 320–326 (2002).

    PubMed  Google Scholar 

  91. T. Ookawara, N. Kawamura, Y. Kitagawa, and N. Taniguchi, Site-specific and random fragmentation of Cu,Zn-superoxide dismutase by glycation reaction. Implication of reactive oxygen species. J. Biol.Chem. 267, 18505–18510 (1992).

    PubMed  Google Scholar 

  92. M. Asahi, J. Fujii, K. Suzuki, H. G. Seo, T. Kuzuya, M. Hori, M. Tada, S. Fujii, and N. Taniguchi, Inactivation of glutathione peroxidase by nitric oxide. Implication for cytotoxicity. J. Biol. Chem. 270, 21035–21039 (1995).

    PubMed  Google Scholar 

  93. H. E. M. McMahon, A. Mangé, N. Nishida, C. Créminon, D. Casanova, and S. Lehmann, Cleavage of the amino terminus of the prion protein by reactive oxygen species. J. Biol. Chem. 276, 2286–2291 (2001).

    PubMed  Google Scholar 

  94. D. R. Brown, PrPSc-like prion protein peptide inhibits the function of cellular prion protein. Biochem. J. 352, 511–518 (2000).

    PubMed  Google Scholar 

  95. W. Rachidi, A. Mangé, A. Senator, P. Guiraud, J. Riondel, M. Benboubetra, A. Favier, and S. Lehmann, Prion infection impairs copper binding of cultured cells. J. Biol.Chem. 278, 14595–14598 (2003).

    PubMed  Google Scholar 

  96. A. M. Thackray, R. Knight, S. J. Haswell, R. Bujdoso, and D. R. Brown, Metal imbalance and compromised antioxidant function are early changes in prion disease. Biochem. J. 362, 253–258 (2002).

    PubMed  Google Scholar 

  97. B.-S. Wong, S. G. Chen, M. Colucci, Z. Xie, T. Pan, T. Liu, R. Li, P. Gambetti, M.-S. Sy, and D. R. Brown, Aberrant metal binding by prion protein in human prion disease. J. Neurochem. 78, 1400–1408 (2001).

    PubMed  Google Scholar 

  98. N. A. Simonian and J. T. Coyle, Oxidative stress in neurodegenerative diseases. Annu. Rev. Pharmacol. Toxicol. 36, 83–106 (1996).

    PubMed  Google Scholar 

  99. P. S. Sastry and K. S. Rao, Apoptosis and the nervous system. J. Neurochem. 74, 1–20 (2000).

    PubMed  Google Scholar 

  100. J. F. Kerr, A. H. Wyllie, and A. R. Currie, Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26, 239–257 (1972).

    PubMed  Google Scholar 

  101. M. Raffray and G. M. Cohen, Apoptosis and necrosis in toxicology: a continuum or distinct modes of cell death? Pharmacol. Ther. 75, 153–177 (1997).

    PubMed  Google Scholar 

  102. G. M. Cohen, X. M. Sun, R. T. Snowden, D. Dinsdale, and D. N. Skilleter, Key morphological features of apoptosis may occur in the absence of internucleosomal DNA fragmentation. Biochem. J. 286, 331–334 (1992).

    PubMed  Google Scholar 

  103. E. Falcieri, A. M. Martelli, R. Bareggi, A. Cataldi, and L. Cocco, The protein kinase inhibitor staurosporine induces morphological changes typical of apoptosis in MOLT-4cells without concomitant DNA fragmentation. Biochem. Biophys. Res. Commun. 193, 19–25 (1993).

    PubMed  Google Scholar 

  104. Z. F. Zakeri, D. Quaglino, T. Latham, and R. A. Lockshin, Delayed internucleosomal DNA fragmentation in programmed cell death. FASEB J. 7, 470–478 (1993).

    PubMed  Google Scholar 

  105. M. K. Collins, J. Marvel, P. Malde, and A. Lopez-Rivas, Interleukin 3 protects murine bone marrow cells from apoptosis induced by DNA damaging agents. J. Exp. Med. 176, 1043–1051 (1992).

    PubMed  Google Scholar 

  106. K. Fukuda, M. Kojiro, and J. F. Chiu, Demonstration of extensive chromatin cleavage in transplanted Morris hepatoma 7777 tissue: apoptosis or necrosis? Am. J. Pathol. 142, 935–946 (1993).

    PubMed  Google Scholar 

  107. Y. Gavrieli, Y Sherman, and S. A. Ben-Sasson, Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J. Cell Biol. 119, 493–501 (1992).

    PubMed  Google Scholar 

  108. I. Ferrer, Nuclear DNA fragmentation in Creutzfeldt-Jakob disease: does a mere positive in situ nuclear end-labeling indicate apoptosis? Acta Neuropathol. 97, 5–12 (1999).

    PubMed  Google Scholar 

  109. H. M. Schätzl, L. Laszlo, D. M. Holtzman, J. Tatzelt, S. J. DeArmond, R. I. Weiner, W. C. Mobley, and S. B. Prusiner, A hypothalamic neuronal cell line persistently infected with scrapie prions exhibits apoptosis. J. Virol. 71, 8821–8831 (1997).

    PubMed  Google Scholar 

  110. A. Bürkle, H. A. Kretzschmar, and D. R. Brown, Poly(ADP-ribose) immunostaining to detect apoptosis induced by a neurotoxic fragment of prion protein. Histochem. J. 31, 711–716 (1999).

    PubMed  Google Scholar 

  111. A. Giese, M. H. Groschup, B. Hess, and H. A. Kretzschmar, Neuronal cell death in scrapie-infected mice is due to apoptosis. Brain Pathol. 5, 213–221 (1995).

    PubMed  Google Scholar 

  112. P. J. Lucassen, A. Williams, W. C. Chung, and H. Fraser, Detection of apoptosis in murine scrapie. Neurosci. Lett. 198, 185–188 (1995).

    PubMed  Google Scholar 

  113. A. Williams, P. J. Lucassen, D. Ritchie, and M. Bruce, PrP deposition, microglial activation, and neuronal apoptosis in murine scrapie. Exp. Neurol. 144, 433–438 (1997).

    PubMed  Google Scholar 

  114. A. Giese, D. R. Brown, M. H. Groschup, C. Feldmann, I. Haist, and H. A. Kretzschmar, Role of microglia in neuronal cell death in prion disease. Brain Pathol. 8, 449–457 (1998).

    PubMed  Google Scholar 

  115. D. Jesionek-Kupnicka, J. Buczynski, R. Kordek, and P.P. Liberski, Neuronal lossand apoptosis in experimental Creutzfeldt-Jakob disease in mice. Folia Neuropathol. 37, 283–286 (1999).

    PubMed  Google Scholar 

  116. D. W. Fairbairn, K. G. Carnahan, R. N. Thwaits, R. V Grigsby, G. R. Holyoak, and K. L. O’Neill, Detection of apoptosis induced DNA cleavage in scrapie-infected sheep brain. FEMS Microbiol. Lett. 115, 341–346 (1994).

    PubMed  Google Scholar 

  117. F. Gray, F. Chretien, H. Adle-Biassette, A. Dorandeu, T. Ereau, M. B. Delisle, N. Kopp, J. W. Ironside, and C. Vital, Neuronal apoptosis in Creutzfeldt-Jakob disease. J. Neuropathol. Exp. Neurol. 58, 321–328 (1999).

    PubMed  Google Scholar 

  118. A. R. White, R. Guirguis, M. W. Brazier, M. F. Jobling, A. F. Hill, K. Beyreuther, C. J. Barrow, C. L. Masters, S. J. Collins, and R. Cappai, Sublethal concentrations of prion peptide PrP106–126 or the amyloid beta peptide of Alzheimer’s disease activates expression of proapoptotic markers in primary cortical neurons. Neurobiol. Dis. 8, 299–316 (2001).

    PubMed  Google Scholar 

  119. C. N. O’Donovan, D. Tobin, and T. G. Cotter, Prion protein fragment PrP-(106–126) induces apoptosis via mitochondrial disruption in human neuronal SH-SY5Y cells. J. Biol. Chem. 276, 43516–43523 (2001).

    PubMed  Google Scholar 

  120. C. Hetz, M. Russelakis-Carneiro, K. Maundrell, J. Castilla, and C. Soto, Caspase-12 and endoplasmic reticulum stress mediate neurotoxicity of pathological prion protein. EMBO J. 22, 5435–5445 (2003).

    PubMed  Google Scholar 

  121. A. Corsaro, S. Thellung, V. Villa, D. R. Principe, D. Paludi, S. Arena, E. Millo, D. Schettini, G. Damonte, A. Aceto, G. Schettini, and T Florio, Prion protein fragment 106–126 inducesa p38 MAP kinase-dependent apoptosis in SH-SY5Y neuroblastoma cells independently from the amyloid fibril formation. Ann. N Y Acad. Sci. 1010, 610–622 (2003).

    PubMed  Google Scholar 

  122. A. E. Williams, L. J. Lawson, V. H. Perry, and H. Fraser, Characterization of the microglial response in murine scrapie. Neuropathol. Appl. Neurobiol. 20, 47–55 (1994).

    PubMed  Google Scholar 

  123. S. Betmouni, V. H. Perry, and J. L. Gordon, Evidence for an early inflammatory response in the central nervous system of mice with scrapie. Neuroscience 74, 1–5 (1996).

    PubMed  Google Scholar 

  124. D. E. McFarlin, M. C. Raff, E. Simpson, and S. H. Nehlsen, Scrapie in immunologically deficient mice. Nature 233, 336 (1971).

    Google Scholar 

  125. A. Sasaki, J. Hirato, and Y. Nakazato, Immunohistochemical study of microglia in the Creutzfeldt-Jakob diseased brain. Acta Neuropathol. 86, 337–344 (1993).

    PubMed  Google Scholar 

  126. H. Mühleisen, J. Gehrmann, and R. Meyermann, Reactive microglia in Creutzfeldt-Jakob disease. Neuropathol. Appl. Neurobiol. 21, 505–517 (1995).

    PubMed  Google Scholar 

  127. C. A. Baker, Z. Y. Lu, I. Zaitsev, and L. Manuelidis, Microglial activation varies in different models of Creutzfeldt-Jakob disease. J. Virol. 73, 5089–5097 (1999).

    PubMed  Google Scholar 

  128. D. R. Brown, Mayhem of the multiple mechanisms: modelling neurodegeneration in prion disease. J. Neurochem. 82, 209–215 (2002).

    PubMed  Google Scholar 

  129. V. H. Perry, C. Cunningham, and D. Boche, Atypical inflammation in the central nervous system in prion disease. Curr. Opin. Neurol. 15, 349–354 (2002).

    PubMed  Google Scholar 

  130. V. A. Fadok, D. L. Bratton, A. Konowal, P. W. Freed, J. Y Westcott, and P. M. Henson, Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-ß, PGE2, and PAF. J. Clin. Invest. 101, 890–898 (1998).

    PubMed  Google Scholar 

  131. A. Williams, A.-M. Van Dam, D. Ritchie, P. Eikelenboom, and H. Fraser, Immunocytochemical appearance of cytokines, prostaglandin E2 and lipocortin-1 in the CNS during the incubation period of murine scrapie correlates with progressive PrP accumulations. Brain Res. 754, 171–180 (1997).

    PubMed  Google Scholar 

  132. C. Cunningham, D. Boche, and V. H. Perry, Transforming growth factor ß1, the dominant cytokine in murine prion disease: influence on inflammatory cytokine synthesis and alteration of vascular extracellular matrix. Neuropathol. Appl. Neurobiol. 28, 107–119 (2002).

    PubMed  Google Scholar 

  133. J.-M. Peyrin, C. I. Lasmézas, S. Haïk, F. Tagliavini, M. Salmona, A. Williams, D. Richie, J.-P. Deslys, and D. Dormont, Microglial cells respond to amyloidogenic PrP peptide by the production of inflammatory cytokines. Neuroreport 10, 723–729 (1999).

    PubMed  Google Scholar 

  134. C. Bate, S. Reid, and A. Williams, Killing of prion-damaged neurones by microglia. Neuroreport 12, 2589–2594 (2001).

    PubMed  Google Scholar 

  135. C. Bate, R. S. Boshuizen, J. P. M. Langeveld, and A. Williams, Temporal and spatial relationship between the death of PrP-damaged neurones and microglial activation. Neuroreport 13, 1695–1700 (2002).

    PubMed  Google Scholar 

  136. A. R. Brown, J. Webb, S. Rebus, R. Walker, A. Williams, and J. K. Fazakerley Inducible cytokine gene expression in the brain in the ME7/CV mouse model of scrapie is highly restricted, is at astrikingly low level relative to the degree of gliosis and occurs only late in the disease. J. Gen. Virol. 84, 2605–2611 (2003).

    PubMed  Google Scholar 

  137. N. A. Mabbott, A. Williams, C. F. Farquhar, M. Pasparakis, G. Kollias, and M. E. Bruce, Tumor necrosis factor alpha-deficient, but not interleukin-6-deficient, mice resist peripheral infection with scrapie. J. Virol. 74, 3338–3344 (2000).

    PubMed  Google Scholar 

  138. M. I. Combrinck, V. H. Perry, and C. Cunningham, Peripheral infection evokes exaggerated sickness behaviour in pre-clinical murine prion disease. Neuroscience 112, 7–11 (2002).

    PubMed  Google Scholar 

  139. V.H. Perry, T.A. Newman, and C. Cunningham, The impact of systemic infection on the progression of neurodegenerative disease. Nat. Rev. Neurosci. 4, 103–112 (2003).

    PubMed  Google Scholar 

  140. V. H. Perry, The influence of systemic inflammation on inflammation in the brain: implications for chronic neurodegenerative disease. Brain Behav. Immun. 18, 407–413 (2004).

    PubMed  Google Scholar 

  141. J. Ciesielski-Treska, N. J. Grant, G. Ulrich, M. Corrotte, Y Bailly, A.-M. Haeberle, S. Chasserot-Golaz, and M.-F. Bader, Fibrillar prion peptide (106–126) and scrapie prion protein hamper phagocytosis in microglia. Glia 46, 101–115 (2004).

    PubMed  Google Scholar 

  142. C. D. Collard, R. Lekowski, J. E. Jordan, A. Agah, and G. L. Stahl, Complement activation following oxidative stress. Mol. Immunol. 36, 941–948 (1999).

    PubMed  Google Scholar 

  143. P. Eikelenboom, C. Bate, W. A. Van Gool, J. J. M. Hoozemans, J. M. Rozemuller, R. Veerhuis, and A. Williams, Neuroinflammation in Alzheimer’s disease and prion disease. Glia 40, 232–239 (2002).

    Article  PubMed  Google Scholar 

  144. P. Gasque, Y. D. Dean, E. P. McGreal, J. VanBeek, and B. P. Morgan, Complement components of the innate immune system in health and disease in the CNS. Immunopharmacology 49, 171–186 (2000).

    PubMed  Google Scholar 

  145. T. Ishii, S. Haga, S. Yagishita, and J. Tateishi, The presence of complements in amyloid plaques of Creutzfeldt-Jakob disease and Gerstmann-Straussler-Scheinker disease. Appl. Pathol. 2, 370–379 (1984).

    PubMed  Google Scholar 

  146. G. G. Kovacs, P. Gasque, T. Ströbel, E. Lindeck-Pozza, M. Strohschneider, J. W. Ironside, H. Budka, and M. Guentchev, Complement activation in human prion disease. Neurobiol. Dis. 15, 21–28 (2004).

    PubMed  Google Scholar 

  147. W. Vogt, B. Damerau, I. von Zabern, R. Nolte, and D. Brunahl, Non-enzymic activation of the fifth component of human complement, by oxygen radicals. Some properties of the activation product, C5b-Iike C5. Mol. Immunol. 26, 1133–1142 (1989).

    PubMed  Google Scholar 

  148. C. D. Collard, A. Väkevä, M. A. Morrissey, A. Agah, S. A. Rollins, W. R. Reenstra, J. A. Buras, S. Meri, and G. L. Stahl, Complement activation after oxidative stress. Role of the lectin complement pathway. Am. J. Pathol. 156, 1549–1556 (2000).

    PubMed  Google Scholar 

  149. M. L. Hart, M. C. Walsh, and G. L. Stahl, Initiation of complement activation following oxidative stress. In vitro and in vivo observations. Mol. Immunol. 41, 165–171 (2004).

    PubMed  Google Scholar 

  150. S. Adler, P. J. Baker, R. J. Johnson, R. F. Ochi, P. Pritzl, and W. G. Couser, Complement membrane attack complex stimulates production of reactive oxygen metabolites by cultured rat mesangial cells. J. Clin. Invest. 77, 762–767 (1986).

    PubMed  Google Scholar 

  151. J. Elsner, M. Oppermann, W. Czech, G. Dobos, E. Schöpf, J. Norgauer, and A. Kapp, C3a activates reactive oxygen radical species production and intracellular calcium transients in human eosinophils. Eur. J. Immunol. 24, 518–522 (1994).

    PubMed  Google Scholar 

  152. N. A. Mabbott, M. E. Bruce, M. Botto, M. J. Walport, and M. B. Pepys, Temporary depletion of complement component C3 or genetic deficiency of C1q significantly delays onset of scrapie. Nat. Med. 7, 485–487 (2001).

    PubMed  Google Scholar 

  153. M. A. Klein, P. S. Kaeser, P. Schwarz, H. Weyd, I. Xenarios, R. M. Zinkemagel, M. C. Carroll, J. S. Verbeek, M. Botto, M. J. Walport, H. Molina, U. Kalinke, H. Acha-Orbea, and A. Aguzzi, Complement facilitates early prion pathogenesis. Nat. Med. 7, 488–492 (2001).

    PubMed  Google Scholar 

  154. B. Hay, S. B. Prusiner, and V. R. Lingappa, Evidence for a secretory form of the cellular prion protein. Biochemistry 26, 8110–8115 (1987).

    PubMed  Google Scholar 

  155. B. Hay, R. A. Barry, I. Lieberburg, S. B. Prusiner, and V. R. Lingappa, Biogenesis and transmembrane orientation of the cellular isoform of the scrapie prion protein. Mol. Cell. Biol. 7, 914–920 (1987).

    PubMed  Google Scholar 

  156. R. S. Hegde, P. Tremblay, D. Groth, S. J. DeArmond, S. B. Prusiner, and V. R. Lingappa, Transmissible and genetic prion diseases share a common pathway of neurodegeneration. Nature 402, 822–826 (1999).

    PubMed  Google Scholar 

  157. R. S. Stewart and D. A. Harris, Most pathogenic mutations do not alter the membrane topology of the prion protein. J. Biol. Chem. 276, 2212–2220 (2001).

    PubMed  Google Scholar 

  158. R. S. Stewart and D. A. Harris, Mutational analysis of topological determinants in prion protein (PrP) and measurement of transmembrane and cytosolic PrP during prion infection. J. Biol. Chem. 278, 45960–45968 (2003).

    PubMed  Google Scholar 

  159. R. S. Stewart, B. Drisaldi, and D. A. Harris, A transmembrane form of the prion protein contains an uncleaved signal peptide and is retained in the endoplasmic reticulum. Mol. Biol. Cell 12, 881–889 (2001).

    PubMed  Google Scholar 

  160. D. A. Harris, Trafficking, turnover and membrane topology of PrP. Br. Med. Bull. 66, 71–85 (2003).

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2005 Springer Science+Business Media, Inc.

About this chapter

Cite this chapter

Unterberger, U., Voigtländer, T., Budka, H. (2005). Central Pathogenesis of Prion Diseases. In: Brown, D.R. (eds) Neurodegeneration and Prion Disease. Springer, Boston, MA. https://doi.org/10.1007/0-387-23923-5_3

Download citation

Publish with us

Policies and ethics