Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Insights into prion strains and neurotoxicity

Key Points

  • Transmissible spongiform encephalopathies (TSEs) are neurodegenerative diseases of humans and many animal species that are caused by prions. The main constituent of prions is scrapie prion protein (PrPSc), an aggregated moiety of the host-derived membrane glycolipoprotein cellular prion protein (PrPC). Although PrPC is encoded by the host genome, prions were found to encipher many phenotypic TSE variants, known as prion strains.

  • Prion strains are TSE isolates that, when inoculated into new hosts, consistently cause disease with specific characteristics, such as incubation period, patterns of PrPSc distribution and relative severity of spongiform changes in the brain (the lesion profile).The agent-specified information of prion strains is thought to be contained within distinct conformations of various PrPSc isotypes.

  • Prions exert their destructive effects predominantly, if not exclusively, within the central nervous system. However, the direct cause of neurotoxicity remains unclear. PrPC is required for prion replication because mice that lack PrPC are resistant to prions. The presence of PrPC on neurons is a prerequisite for prion-induced neurotoxicity.

  • A series of transgenic mice that express various prion protein mutants indicate that deletion of specific regions of PrPC can render it neurotoxic. This toxicity is modulated by co-expression of wild-type PrPC.

  • Currently, there is no reagent allowing non-invasive, pre-mortem diagnosis of prion diseases. In view of recent unfortunate cases of Creutzfeldt–Jakob disease infection through blood transfusion, reliable, specific and, most importantly, sensitive reagents are urgently needed.

Abstract

Transmissible spongiform encephalopathies (TSEs) are neurodegenerative diseases that are caused by prions and affect humans and many animal species. It is now widely accepted that the infectious agent that causes TSEs is PrPSc, an aggregated moiety of the host-derived membrane glycolipoprotein PrPC. Although PrPC is encoded by the host genome, prions themselves encipher many phenotypic TSE variants, known as prion strains. Prion strains are TSE isolates that, after inoculation into distinct hosts, cause disease with consistent characteristics, such as incubation period, distinct patterns of PrPSc distribution and spongiosis and relative severity of the spongiform changes in the brain. The existence of such strains poses a fascinating challenge to prion research.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Incidence of BSE and vCJD cases reported worldwide.
Figure 2: Models of prion strain variation and species barrier phenomena.
Figure 3: Model of how glycosylation ratios might determine the structure of infectious prion protein seeds.
Figure 4: Do different PrPSc types in patients with sCJD and vCJD represent different prion strains?
Figure 5: Hypothetical model for the effects of PrPC and its variants.

Similar content being viewed by others

References

  1. Glatzel, M. et al. Human prion diseases: epidemiology and integrated risk assessment. Lancet Neurol. 2, 757–763 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. Collins, P. S., Lawson, V. A. & Masters, P. C. Transmissible spongiform encephalopathies. Lancet 363, 51–61 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. Prusiner, S. B. Novel proteinaceous infectious particles cause scrapie. Science 216, 136–144 (1982). Enunciation of the 'protein-only' hypothesis and definition of the prion.

    Article  CAS  PubMed  Google Scholar 

  4. Griffith, J. S. Self-replication and scrapie. Nature 215, 1043–1044 (1967). First communication of the 'protein-only' hypothesis.

    Article  CAS  PubMed  Google Scholar 

  5. Aguzzi, A. & Heikenwalder, M. Prion diseases: cannibals and garbage piles. Nature 423, 127–129 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Oesch, B., Groth, D. F., Prusiner, S. B. & Weissmann, C. Search for a scrapie-specific nucleic acid: a progress report. Ciba Found. Symp. 135, 209–223 (1988).

    CAS  PubMed  Google Scholar 

  7. Oesch, B. et al. A cellular gene encodes scrapie PrP 27–30 protein. Cell 40, 735–746 (1985).

    Article  CAS  PubMed  Google Scholar 

  8. Prusiner, S. B. Creutzfeldt-Jakob disease and scrapie prions. Alzheimer Dis. Assoc. Disord. 3, 52–78 (1989).

    Article  CAS  PubMed  Google Scholar 

  9. Weissmann, C. A 'unified theory' of prion propagation. Nature 352, 679–683 (1991).

    Article  CAS  PubMed  Google Scholar 

  10. Büeler, H. R. et al. Mice devoid of PrP are resistant to scrapie. Cell 73, 1339–1347 (1993). Demonstration that Prnp0/0 mice are resistant to prion disease.

    Article  PubMed  Google Scholar 

  11. Aguzzi, A. & Polymenidou, M. Mammalian prion biology. One century of evolving concepts. Cell 116, 313–327 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Zhang, C. C., Steele, A. D., Lindquist, S. & Lodish, H. F. Prion protein is expressed on long-term repopulating hematopoietic stem cells and is important for their self-renewal. Proc. Natl Acad. Sci. USA 103, 2184–2189 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Steele, A. D., Emsley, J. G., Ozdinler, P. H., Lindquist, S. & Macklis, J. D. Prion protein (PrPc) positively regulates neural precursor proliferation during developmental and adult mammalian neurogenesis. Proc. Natl Acad. Sci. USA 103, 3416–3421 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Silveira, J. R. et al. The most infectious prion protein particles. Nature 437, 257–261 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Telling, G. C. et al. Prion propagation in mice expressing human and chimeric PrP transgenes implicates the interaction of cellular PrP with another protein. Cell 83, 79–90 (1995).

    Article  CAS  PubMed  Google Scholar 

  16. Priola, S. A., Chesebro, B. & Caughey, B. Biomedicine. A view from the top – prion diseases from 10,000 feet. Science 300, 917–919 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Bolton, D. C., McKinley, M. P. & Prusiner, S. B. Identification of a protein that purifies with the scrapie prion. Science 218, 1309–1311 (1982).

    Article  CAS  PubMed  Google Scholar 

  18. Safar, J. G. et al. Measuring prions causing bovine spongiform encephalopathy or chronic wasting disease by immunoassays and transgenic mice. Nature Biotech. 20, 1147–1150 (2002).

    Article  CAS  Google Scholar 

  19. Sigurdson, C. J. et al. Strain fidelity of chronic wasting disease upon murine adaptation. J. Virol. 80, 12303–12311 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Richt, J. A. et al. Characterization of the recent U.S. BSE case and methods for surveillance. Proc. Annu. Meet. US Anim. Health Assoc. 108, 91–92 (2004).

    Google Scholar 

  21. Heikenwalder, M. et al. Chronic lymphocytic inflammation specifies the organ tropism of prions. Science 307, 1107–1110 (2005). Inflammatory conditions support prion replication in otherwise prion-free organs.

    Article  CAS  PubMed  Google Scholar 

  22. Seeger, H. et al. Coincident scrapie infection and nephritis lead to urinary prion excretion. Science 310, 324–326 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Ligios, C. et al. PrPSc in mammary glands of sheep affected by scrapie and mastitis. Nature Med. 11, 1137–1138 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Houston, F., Foster, J. D., Chong, A., Hunter, N. & Bostock, C. J. Transmission of BSE by blood transfusion in sheep. Lancet 356, 999–1000 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Mathiason, C. K. et al. Infectious prions in the saliva and blood of deer with chronic wasting disease. Science 314, 133–136 (2006).

    Article  CAS  PubMed  Google Scholar 

  26. Llewelyn, C. A. et al. Possible transmission of variant Creutzfeldt–Jakob disease by blood transfusion. Lancet 363, 417–421 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Peden, A. H., Head, M. W., Ritchie, D. L., Bell, J. E. & Ironside, J. W. Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet 364, 527–529 (2004). A case report of accidental CJD transmission through blood transfusion.

    Article  PubMed  Google Scholar 

  28. Wroe, S. J. et al. Clinical presentation and pre-mortem diagnosis of variant Creutzfeldt–Jakob disease associated with blood transfusion: a case report. Lancet 368, 2061–2067 (2006).

    Article  PubMed  Google Scholar 

  29. Aguzzi, A. & Glatzel, M. Prion infections, blood and transfusions. Nature Clin. Pract. Neurol. 2, 321–329 (2006).

    Article  CAS  Google Scholar 

  30. Safar, J. et al. Eight prion strains have PrPSc molecules with different conformations. Nature Med. 4, 1157–1165 (1998).

    Article  CAS  PubMed  Google Scholar 

  31. Nonno, R. et al. Efficient transmission and characterization of Creutzfeldt–Jakob disease strains in bank voles. PLoS Pathog. 2, e12 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Shorter, J. & Lindquist, S. Prions as adaptive conduits of memory and inheritance. Nature Rev. Genet. 6, 435–450 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Wickner, R. B., Edskes, H. K., Roberts, B. T., Pierce, M. & Baxa, U. Prions of yeast as epigenetic phenomena: high protein 'copy number' inducing protein 'silencing'. Adv. Genet. 46, 485–525 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. Aguzzi, A. Understanding the diversity of prions. Nature Cell Biol. 6, 290–292 (2004).

    Article  CAS  PubMed  Google Scholar 

  35. Pattison, I. H. & Millson, G. C. Scrapie produced experimentally in goats with special reference to the clinical syndrome. J. Comp. Pathol. 71, 101–108 (1961).

    Article  CAS  PubMed  Google Scholar 

  36. Fraser, H. & Dickinson, A. G. Scrapie in mice. Agent-strain differences in the distribution and intensity of grey matter vacuolation. J. Comp. Pathol. 83, 29–40 (1973).

    Article  CAS  PubMed  Google Scholar 

  37. Bruce, M. E. & Dickinson, A. G. Biological evidence that scrapie agent has an independent genome. J. Gen. Virol. 68, 79–89 (1987).

    Article  PubMed  Google Scholar 

  38. Kimberlin, R. H., Cole, S. & Walker, C. A. Temporary and permanent modifications to a single strain of mouse scrapie on transmission to rats and hamsters. J. Gen. Virol. 68, 1875–1881 (1987).

    Article  PubMed  Google Scholar 

  39. Race, R. et al. Subclinical scrapie infection in a resistant species: persistence, replication, and adaptation of infectivity during four passages. J. Infect. Dis. 186 (Suppl. 2), S166–S170 (2002).

    Article  PubMed  Google Scholar 

  40. Hill, A. F. & Collinge, J. Subclinical prion infection in humans and animals. Br. Med. Bull. 66, 161–170 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Hill, A. F. et al. Species-barrier-independent prion replication in apparently resistant species. Proc. Natl Acad. Sci. USA 29, 10248–10253 (2000).

    Article  Google Scholar 

  42. Collinge, J. et al. Unaltered susceptibility to BSE in transgenic mice expressing human prion protein. Nature 378, 779–783 (1995).

    Article  CAS  PubMed  Google Scholar 

  43. Scott, M. R. et al. Compelling transgenetic evidence for transmission of bovine spongiform encephalopathy prions to humans. Proc. Natl Acad. Sci. USA 96, 15137–151342 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Scott, M. R., Peretz, D., Nguyen, H. O., Dearmond, S. J. & Prusiner, S. B. Transmission barriers for bovine, ovine, and human prions in transgenic mice. J. Virol. 79, 5259–5271 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Scott, M. et al. Transgenic mice expressing hamster prion protein produce species-specific scrapie infectivity and amyloid plaques. Cell 59, 847–857 (1989).

    Article  CAS  PubMed  Google Scholar 

  46. Vilotte, J. L. et al. Markedly increased susceptibility to natural sheep scrapie of transgenic mice expressing ovine PrP. J. Virol. 75, 5977–5984 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Collinge, J., Sidle, K. C., Meads, J., Ironside, J. & Hill, A. F. Molecular analysis of prion strain variation and the aetiology of 'new variant' CJD. Nature 383, 685–690 (1996).

    Article  CAS  PubMed  Google Scholar 

  48. Collinge, J. Molecular neurology of prion disease. J. Neurol. Neurosurg. Psychiatr. 76, 906–919 (2005).

    Article  CAS  Google Scholar 

  49. Khalili-Shirazi, A. et al. PrP glycoforms are associated in a strain-specific ratio in native PrPSc. J. Gen. Virol. 86, 2635–2644 (2005).

    Article  CAS  PubMed  Google Scholar 

  50. DeArmond, S. J. et al. Selective neuronal targeting in prion disease. Neuron 19, 1337–1348 (1997).

    Article  CAS  PubMed  Google Scholar 

  51. Neuendorf, E. et al. Glycosylation deficiency at either one of the two glycan attachment sites of cellular prion protein preserves susceptibility to bovine spongiform encephalopathy and scrapie infections. J. Biol. Chem. 279, 53306–53316 (2004).

    Article  CAS  PubMed  Google Scholar 

  52. Cancellotti, E. et al. Altered glycosylated PrP proteins can have different neuronal trafficking in brain but do not acquire scrapie-like properties. J. Biol. Chem. 280, 42909–42918 (2005).

    Article  CAS  PubMed  Google Scholar 

  53. Bessen, R. A. & Marsh, R. F. Distinct PrP properties suggest the molecular basis of strain variation in transmissible mink encephalopathy. J. Virol. 68, 7859–7868 (1994). Describes the differentiation of prion strains by proteolytic digest.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Bessen, R. A. et al. Non-genetic propagation of strain-specific properties of scrapie prion protein. Nature 375, 698–700 (1995).

    Article  CAS  PubMed  Google Scholar 

  55. Telling, G. C. et al. Evidence for the conformation of the pathologic isoform of the prion protein enciphering and propagating prion diversity. Science 274, 2079–2082 (1996).

    Article  CAS  PubMed  Google Scholar 

  56. Parchi, P. et al. Genetic influence on the structural variations of the abnormal prion protein. Proc. Natl Acad. Sci. USA 97, 10168–10172 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Zanusso, G. et al. Identification of distinct N-terminal truncated forms of prion protein in different Creutzfeldt–Jakob disease subtypes. J. Biol. Chem. 279, 38936–38942 (2004).

    Article  CAS  PubMed  Google Scholar 

  58. Bruce, M. E. et al. Transmissions to mice indicate that 'new variant' CJD is caused by the BSE agent. Nature 389, 498–501 (1997).

    Article  CAS  PubMed  Google Scholar 

  59. Palmer, M. S., Dryden, A. J., Hughes, J. T. & Collinge, J. Homozygous prion protein genotype predisposes to sporadic Creutzfeldt–Jakob disease. Nature 352, 340–342 (1991).

    Article  CAS  PubMed  Google Scholar 

  60. Collinge, J., Palmer, M. S. & Dryden, A. J. Genetic predisposition to iatrogenic Creutzfeldt–Jakob disease. Lancet 337, 1441–1442 (1991).

    Article  CAS  PubMed  Google Scholar 

  61. Puoti, G. et al. Sporadic Creutzfeldt–Jakob disease: co-occurrence of different types of PrPSc in the same brain. Neurology 53, 2173–2176 (1999).

    Article  CAS  PubMed  Google Scholar 

  62. Dickson, D. W. & Brown, P. Multiple prion types in the same brain: is a molecular diagnosis of CJD possible?. Neurology 53, 1903–1904 (1999).

    Article  CAS  PubMed  Google Scholar 

  63. Polymenidou, M. et al. Coexistence of multiple PrPSc types in individuals with Creutzfeldt–Jakob disease. Lancet Neurol. 4, 805–814 (2005).

    Article  CAS  PubMed  Google Scholar 

  64. Yull, H. M. et al. Detection of type 1 prion protein in variant Creutzfeldt–Jakob disease. Am. J. Pathol. 168, 151–157 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Nishida, N., Katamine, S. & Manuelidis, L. Reciprocal interference between specific CJD and scrapie agents in neural cell cultures. Science 310, 493–496 (2005).

    Article  CAS  PubMed  Google Scholar 

  66. Bartz, J. C. et al. Prion interference is due to a reduction in strain-specific PrPSc levels. J. Virol. 81, 689–697 (2007).

    Article  CAS  PubMed  Google Scholar 

  67. Dickinson, A. G., Fraser, H., Meikle, V. M. & Outram, G. W. Competition between different scrapie agents in mice. Nature New Biol. 237, 244–245 (1972).

    Article  CAS  PubMed  Google Scholar 

  68. Manuelidis, L. Vaccination with an attenuated Creutzfeldt–Jakob disease strain prevents expression of a virulent agent. Proc. Natl Acad. Sci. USA 95, 2520–2525 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Casalone, C. et al. Identification of a second bovine amyloidotic spongiform encephalopathy: molecular similarities with sporadic Creutzfeldt–Jakob disease. Proc. Natl Acad. Sci. USA 101, 3065–3070 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Beringue, V. et al. Isolation from cattle of a prion strain distinct from that causing bovine spongiform encephalopathy. PLoS Pathog. 2, e112 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Meyer-Luehmann, M. et al. Exogenous induction of cerebral β-amyloidogenesis is governed by agent and host. Science 313, 1781–1784 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Aguzzi, A. & Haass, C. Games played by rogue proteins in prion disorders and Alzheimer's disease. Science 302, 814–818 (2003).

    Article  CAS  PubMed  Google Scholar 

  73. Riek, R. Cell biology: infectious Alzheimer's disease? Nature 444, 429–431 (2006).

    Article  CAS  PubMed  Google Scholar 

  74. Aguzzi, A. & Sigurdson, C. J. Antiprion immunotherapy: to suppress or to stimulate? Nature Rev. Immunol. 4, 725–736 (2004).

    Article  CAS  Google Scholar 

  75. Brown, P. et al. Human spongiform encephalopathy: the National Institutes of Health series of 300 cases of experimentally transmitted disease. Ann. Neurol. 35, 513–529 (1994).

    Article  CAS  PubMed  Google Scholar 

  76. Glatzel, M., Abela, E., Maissen, M. & Aguzzi, A. Extraneural pathologic prion protein in sporadic Creutzfeldt–Jakob disease. N. Engl. J. Med. 349, 1812–1820 (2003).

    Article  CAS  PubMed  Google Scholar 

  77. Peden, A. H., Ritchie, D. L., Head, M. W. & Ironside, J. W. Detection and localization of PrPSc in the skeletal muscle of patients with variant, iatrogenic, and sporadic forms of Creutzfeldt–Jakob disease. Am. J. Pathol. 168, 927–935 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Blättler, T. et al. PrP-expressing tissue required for transfer of scrapie infectivity from spleen to brain. Nature 389, 69–73 (1997).

    Article  PubMed  Google Scholar 

  79. Brown, K. L. et al. Scrapie replication in lymphoid tissues depends on prion protein- expressing follicular dendritic cells. Nature Med. 5, 1308–1312 (1999).

    Article  CAS  PubMed  Google Scholar 

  80. Bartz, J. C., Dejoia, C., Tucker, T., Kincaid, A. E. & Bessen, R. A. Extraneural prion neuroinvasion without lymphoreticular system infection. J. Virol. 79, 11858–11863 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Bessen, R. A. & Marsh, R. F. Biochemical and physical properties of the prion protein from two strains of the transmissible mink encephalopathy agent. J. Virol. 66, 2096–2101 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Telling, G. C. et al. Transmission of Creutzfeldt–Jakob disease from humans to transgenic mice expressing chimeric human–mouse prion protein. Proc. Natl Acad. Sci. USA 91, 9936–9940 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Büeler, H. R. et al. Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature 356, 577–582 (1992).

    Article  PubMed  Google Scholar 

  84. Mallucci, G. R. et al. Post-natal knockout of prion protein alters hippocampal CA1 properties, but does not result in neurodegeneration. EMBO J. 21, 202–210 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Meier, P. et al. Soluble dimeric prion protein binds PrPScin vivo and antagonizes prion disease. Cell 113, 49–60 (2003).

    Article  CAS  PubMed  Google Scholar 

  86. Brandner, S. et al. Normal host prion protein necessary for scrapie-induced neurotoxicity. Nature 379, 339–343 (1996).

    Article  CAS  PubMed  Google Scholar 

  87. Mallucci, G. et al. Depleting neuronal PrP in prion infection prevents disease and reverses spongiosis. Science 302, 871–874 (2003). Describes a role for PrPC in prion-induced neurotoxicity.

    Article  CAS  PubMed  Google Scholar 

  88. Chesebro, B. et al. Anchorless prion protein results in infectious amyloid disease without clinical scrapie. Science 308, 1435–1439 (2005).

    Article  CAS  PubMed  Google Scholar 

  89. Aguzzi, A. Cell biology. Prion toxicity: all sail and no anchor. Science 308, 1420–1421 (2005).

    Article  CAS  PubMed  Google Scholar 

  90. Kimberley, F. C., Sivasankar, B. & Paul Morgan, B. Alternative roles for CD59. Mol. Immunol. 44, 73–81 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. Trifilo, M. J. et al. Prion-induced amyloid heart disease with high blood infectivity in transgenic mice. Science 313, 94–97 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Shmerling, D. et al. Expression of amino-terminally truncated PrP in the mouse leading to ataxia and specific cerebellar lesions. Cell 93, 203–214 (1998).

    Article  CAS  PubMed  Google Scholar 

  93. Radovanovic, I. et al. Truncated prion protein and Doppel are myelinotoxic in the absence of oligodendrocytic PrPC. J. Neurosci. 25, 4879–4888 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Baumann, F. et al. Lethal recessive myelin toxicity of prion protein lacking its central domain. EMBO J. 26, 538–547 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Hegde, R. S. et al. A transmembrane form of the prion protein in neurodegenerative disease. Science 279, 827–834 (1998).

    Article  CAS  PubMed  Google Scholar 

  96. Hegde, R. S. et al. Transmissible and genetic prion diseases share a common pathway of neurodegeneration. Nature 402, 822–826 (1999).

    Article  CAS  PubMed  Google Scholar 

  97. Stewart, R. S., Piccardo, P., Ghetti, B. & Harris, D. A. Neurodegenerative illness in transgenic mice expressing a transmembrane form of the prion protein. J. Neurosci. 25, 3469–3477 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Ma, J., Wollmann, R. & Lindquist, S. Neurotoxicity and neurodegeneration when PrP accumulates in the cytosol. Science 298, 1781–1785 (2002).

    Article  CAS  PubMed  Google Scholar 

  99. Ma, J. & Lindquist, S. Conversion of PrP to a self-perpetuating PrPSc-like conformation in the cytosol. Science 298, 1785–1788 (2002).

    Article  CAS  PubMed  Google Scholar 

  100. Drisaldi, B. et al. Mutant PrP is delayed in its exit from the endoplasmic reticulum, but neither wild-type nor mutant PrP undergoes retrotranslocation prior to proteasomal degradation. J. Biol. Chem. 278, 21732–21743 (2003).

    Article  CAS  PubMed  Google Scholar 

  101. Roucou, X., Guo, Q., Zhang, Y., Goodyer, C. G. & LeBlanc, A. C. Cytosolic prion protein is not toxic and protects against Bax-mediated cell death in human primary neurons. J. Biol. Chem. 278, 40877–40881 (2003).

    Article  CAS  PubMed  Google Scholar 

  102. Barmada, S., Piccardo, P., Yamaguchi, K., Ghetti, B. & Harris, D. A. GFP-tagged prion protein is correctly localized and functionally active in the brains of transgenic mice. Neurobiol. Dis. 16, 527–537 (2004).

    Article  CAS  PubMed  Google Scholar 

  103. Barmada, S. J. & Harris, D. A. Visualization of prion infection in transgenic mice expressing green fluorescent protein-tagged prion protein. J. Neurosci. 25, 5824–5832 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Ford, M. J., Burton, L. J., Morris, R. J. & Hall, S. M. Selective expression of prion protein in peripheral tissues of the adult mouse. Neuroscience 113, 177–192 (2002).

    Article  CAS  PubMed  Google Scholar 

  105. Herms, J. et al. Evidence of presynaptic location and function of the prion protein. J. Neurosci. 19, 8866–8875 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Moser, M., Colello, R. J., Pott, U. & Oesch, B. Developmental expression of the prion protein gene in glial cells. Neuron 14, 509–517 (1995).

    Article  CAS  PubMed  Google Scholar 

  107. Stahl, N., Borchelt, D. R., Hsiao, K. & Prusiner, S. B. Scrapie prion protein contains a phosphatidylinositol glycolipid. Cell 51, 229–240 (1987).

    Article  CAS  PubMed  Google Scholar 

  108. Haraguchi, T. et al. Asparagine-linked glycosylation of the scrapie and cellular prion proteins. Arch. Biochem. Biophys. 274, 1–13 (1989).

    Article  CAS  PubMed  Google Scholar 

  109. Riek, R. et al. NMR structure of the mouse prion protein domain PrP (121–321). Nature 382, 180–182 (1996).

    Article  CAS  PubMed  Google Scholar 

  110. Wuthrich, K. & Riek, R. Three-dimensional structures of prion proteins. Adv. Protein Chem. 57, 55–82 (2001).

    Article  CAS  PubMed  Google Scholar 

  111. Knaus, K. J. et al. Crystal structure of the human prion protein reveals a mechanism for oligomerization. Nature Struct. Biol. 8, 770–774 (2001).

    Article  CAS  PubMed  Google Scholar 

  112. Hornemann, S. et al. Recombinant full-length murine prion protein, mPrP (23–231): purification and spectroscopic characterization. FEBS Lett. 413, 277–281 (1997).

    Article  CAS  PubMed  Google Scholar 

  113. Brown, D. R. et al. The cellular prion protein binds copper in vivo. Nature 390, 684–687 (1997).

    Article  CAS  PubMed  Google Scholar 

  114. Garnett, A. P. & Viles, J. H. Copper binding to the octarepeats of the prion protein. Affinity, specificity, folding, and cooperativity: insights from circular dichroism. J. Biol. Chem. 278, 6795–6802 (2003).

    Article  CAS  PubMed  Google Scholar 

  115. Jones, C. E., Klewpatinond, M., Abdelraheim, S. R., Brown, D. R. & Viles, J. H. Probing copper2+ binding to the prion protein using diamagnetic nickel2+ and 1H NMR: the unstructured N terminus facilitates the coordination of six copper2+ ions at physiological concentrations. J. Mol. Biol. 346, 1393–1407 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  117. Waggoner, D. J. et al. Brain copper content and cuproenzyme activity do not vary with prion protein expression level. J. Biol. Chem. 275, 7455–7458 (2000).

    Article  CAS  PubMed  Google Scholar 

  118. Hutter, G., Heppner, F. L. & Aguzzi, A. No superoxide dismutase activity of cellular prion protein in vivo. Biol. Chem. 384, 1279–1285 (2003).

    Article  CAS  PubMed  Google Scholar 

  119. Enari, M., Flechsig, E. & Weissmann, C. Scrapie prion protein accumulation by scrapie-infected neuroblastoma cells abrogated by exposure to a prion protein antibody. Proc. Natl Acad. Sci. USA 98, 9295–9299 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Peretz, D. et al. Antibodies inhibit prion propagation and clear cell cultures of prion infectivity. Nature 412, 739–743 (2001).

    Article  CAS  PubMed  Google Scholar 

  121. Heppner, F. L. et al. Prevention of scrapie pathogenesis by transgenic expression of anti-prion protein antibodies. Science 294, 178–182 (2001).

    Article  CAS  PubMed  Google Scholar 

  122. White, A. R. et al. Monoclonal antibodies inhibit prion replication and delay the development of prion disease. Nature 422, 80–83 (2003).

    Article  CAS  PubMed  Google Scholar 

  123. Koller, M. F., Grau, T. & Christen, P. Induction of antibodies against murine full-length prion protein in wild-type mice. J. Neuroimmunol. 132, 113–116 (2002).

    Article  CAS  PubMed  Google Scholar 

  124. Sigurdsson, E. M. et al. Immunization delays the onset of prion disease in mice. Am. J. Pathol. 161, 13–17 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Sigurdsson, E. M. et al. Anti-prion antibodies for prophylaxis following prion exposure in mice. Neurosci. Lett. 336, 185–187 (2003).

    Article  CAS  PubMed  Google Scholar 

  126. Tal, Y. et al. Complete Freund's adjuvant immunization prolongs survival in experimental prion disease in mice. J. Neurosci. Res. 71, 286–290 (2003).

    Article  CAS  PubMed  Google Scholar 

  127. Souan, L., Margalit, R., Brenner, O., Cohen, I. R. & Mor, F. Self prion protein peptides are immunogenic in Lewis rats. J. Autoimmun. 17, 303–310 (2001).

    Article  CAS  PubMed  Google Scholar 

  128. Souan, L. et al. Modulation of proteinase-K resistant prion protein by prion peptide immunization. Eur. J. Immunol. 31, 2338–2346 (2001).

    Article  CAS  PubMed  Google Scholar 

  129. Schwarz, A. et al. Immunisation with a synthetic prion protein-derived peptide prolongs survival times of mice orally exposed to the scrapie agent. Neurosci. Lett. 350, 187–189 (2003).

    Article  CAS  PubMed  Google Scholar 

  130. Arbel, M., Lavie, V. & Solomon, B. Generation of antibodies against prion protein in wild-type mice via helix 1 peptide immunization. J. Neuroimmunol. 144, 38–45 (2003).

    Article  CAS  PubMed  Google Scholar 

  131. Gregoire, S. et al. Identification of two immunogenic domains of the prion protein — PrP — which activate class II-restricted T cells and elicit antibody responses against the native molecule. J. Leukoc. Biol. 76, 125–134 (2004).

    Article  CAS  PubMed  Google Scholar 

  132. Rosset, M. B. et al. Breaking immune tolerance to the prion protein using prion protein peptides plus oligodeoxynucleotide-CpG in mice. J. Immunol. 172, 5168–5174 (2004).

    Article  CAS  PubMed  Google Scholar 

  133. Polymenidou, M. et al. Humoral immune response to native eukaryotic prion protein correlates with anti-prion protection. Proc. Natl Acad. Sci. USA 101, 14670–14676 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Lechner, F. et al. Virus-like particles as a modular system for novel vaccines. Intervirology 45, 212–217 (2002).

    Article  PubMed  Google Scholar 

  135. Nikles, D. et al. Circumventing tolerance to the prion protein (PrP): vaccination with PrP-displaying retrovirus particles induces humoral immune responses against the native form of cellular PrP. J. Virol. 79, 4033–4042 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Solforosi, L. et al. Cross-linking cellular prion protein triggers neuronal apoptosis in vivo. Science 303, 1514–1516 (2004).

    Article  CAS  PubMed  Google Scholar 

  137. Nicoll, J. A. et al. Neuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report. Nature Med. 9, 448–452 (2003).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

A.A. is supported by grants from the European Union (TSEUR and Immunoprion), the Swiss National Foundation, the National Center for Competence in Research on neural plasticity and repair, and the Ernst Jung Foundation. M.H. is supported by the Bonizzi–Theler Foundation and the Max Cloëtta Foundation. M.H. and M.P. are supported by the Foundation for Research at the Medical Faculty, University of Zürich, Switzerland.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Adriano Aguzzi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

OMIM

Alzheimer's disease

Creutzfeldt–Jakob disease

Fatal familial insomnia

Gerstmann–Sträussler–Scheinker Syndrome

Kuru

FURTHER INFORMATION

University Hospital Zürich Institute of Neuropathology web site

National Creutzfeldt–Jakob Disease Surveillance Unit web site

Glossary

Transmissible spongiform encephalopathy

(TSE). A synonym for prion disease and a general term that refers to all diseases that are associated with the presence of prions in vacuolated central nervous system tissue. Prions from TSE-affected brains can be transmitted from one affected host to another host.

Prion

An infectious agent with unconventional properties that causes TSE; it is an acronym for 'proteinaceous infectious particle'.

vCJD

(Variant CJD). A type of CJD that is thought to result from the ingestion of beef products that are contaminated with bovine spongiform encephalopathy. The majority of vCJD cases occur in young individuals.

Iatrogenic CJD

CJD transmission from human to human through medical mishaps (for example, transfusion of prion-infected blood).

Familial CJD

Genetic prion diseases that are associated with mutations in one or more loci within the PRNP gene sequence.

Sporadic CJD

The most common CJD, which occurs worldwide at a rate of one case per million people. It mostly affects older adults and the cause is unknown.

'Protein-only' hypothesis

This hypothesis proposes that the prion is devoid of informational nucleic acid and that the essential pathogenic component is a protein or glycoprotein.

Scrapie prion protein

(PrPSc). An abnormal form of the mature PRNP gene product that is found in tissues of patients with TSE, defined as being partially resistant to proteinase-K digestion under standardized conditions. It is believed to differ from PrPC conformationally and is considered to be the main transmissible agent or prion.

Cellular prion protein

(PrPC). The normally occurring form of the mature PRNP gene product, the presence of which is necessary, but not sufficient, for replication of the prion.

Prion strain

A TSE isolate (or source of infection) that, upon inoculation into genetically identical hosts, causes prion disease with consistent characteristics. The agent-specified information in prion strains is thought to be contained in the distinct conformations of various PrPSc isotypes.

Horizontal prion transmission

The spread of disease between individuals in a certain population or flock of animals. The cause of horizontal prion transmission in some cases (such as scrapie in sheep and chronic wasting disease in elk and deer) remains enigmatic.

Bovine spongiform encephalopathy

(BSE). A TSE that primarily affects cattle, which is believed to be caused by animal feed that was contaminated with the prion agent of either scrapie or BSE. First identified in 1986 in the UK, it became an epidemic that affected hundreds of thousands of cattle in Europe.

Chronic wasting disease

(CWD). A TSE of unknown origin that can be contracted by mule deer, white-tailed deer, Rocky Mountain elk and moose. CWD was identified in the early 1980s in the United States with a horizontal transmission of up to 20%.

Scrapie

A TSE that affects sheep and goats. It has been known since at least the eighteenth century, hundreds of years before prions were first defined. Scrapie was shown to be transmissible 60 years ago.

Lymphoreticular system

Part of the immune system. It is divided into primary (bone marrow and thymus) and secondary lymphoid tissues (spleen and lymph nodes).

Ancillary genome

A putative (secondary) genome within the prion that might carry the information necessary for prion replication and disease phenotype. So far, all evidence points against the presence of an ancillary genome within the prion.

Vacuolation

One of the main neuropathological hallmarks of prion diseases, which results from extensive neuronal loss leading to the occurrence of membrane-lined, optically empty intraneuronal organelles (termed vacuoles) within the brain.

CJD types

Distinct isoforms of PrPSc that are associated with different CJD phenotypes. CJD types are biochemically distinguished by the different fragment sizes seen on western blots following treatment with proteinase K, as well as the ratio of PrPSc glycoforms and deposition patterns. In this article, we use the CJD classification that was proposed by Gambetti and colleagues.

Amyloid-β

(Aβ). A hydrophobic peptide of 40–42 amino acids and the main component of amyloid plaques in the brains of patients with Alzheimer's disease. Aβ is a product of pathological cleavage of amyloid precursor protein (APP), a transmembrane protein that naturally occurs in the brain and other tissues of mammals.

Neurotropic

Prion strains that mainly attack the CNS. The prion infectivity of individuals who are infected with neurotropic prion strains is primarily contained within the CNS.

Lymphotropic

Prion strains that replicate in the lymphoreticular system before neuroinvasion. The prion infectivity of individuals who are infected with lymphotropic prion strains is found in peripheral lymphoid tissues and the CNS.

Amyloid deposit

A pathologic protein aggregate that occurs in the brains and other tissues of individuals suffering from amyloid or 'protein-misfolding' diseases. The main constituent of amyloid deposits is characteristic for each disease; for example, PrPSc in prion diseases and amyloid-β in Alzheimer's disease.

Shmerling's disease

A neurodegenerative syndrome that occurs in transgenic mice expressing N-terminally truncated PrPC, presenting with ataxia and cerebellar lesions. It can be reversed by the expression of a single allele of full-length PrPC.

Neuropil

The network made out of neuronal processes (axonal, dendritic and glial) within the grey matter of the CNS.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Aguzzi, A., Heikenwalder, M. & Polymenidou, M. Insights into prion strains and neurotoxicity. Nat Rev Mol Cell Biol 8, 552–561 (2007). https://doi.org/10.1038/nrm2204

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm2204

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing