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.

  • Article
  • Published:

Identification of the prion protein allotypes which accumulate in the brain of sporadic and familial Creutzfeldt-Jakob disease patients

Nature Medicine volume 3, pages 521–525 (1997)Cite this article

Abstract

A characteristic feature of Creutzfeldt-Jakob disease (CJD) is the accumulation in the brain of the amyloid protease-resistant protein PrPsen. PrPres derives from a host-encoded, protease-sensitive isoform, PrPsen. Mutations of this protein are linked to familial variants of the disease, and the presence of a methionine or valine residue at the polymorphic position 129 may be critical in sporadic CJD cases. We found that in the brain of patients heterozygous for the mutation in which isoleucine is substituted for valine at codon 210 (Val210lle), the PrPres is formed by both the wild-type and mutant PrPsen. We also found that in a sporadic CJD patient, who was heterozygous (Met/Val) at position 129, PrPres is also formed by both allotypes. These data associate transmissible spongiform encephalopathies with other amyloidosis, although the nature of the transmissible agent remains unsettled.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Similar content being viewed by others

References

  1. Pocchiari, M. Prions and related neurological diseases. Mol. Aspects Med. 15, 195–291 (1994).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Stahl, N. et al. Structural studies of the scrapie prion protein using mass spectrometry and amino acid sequencing. Biochemistry 32, 1991–2002 (1993).

    Article  CAS  Google Scholar 

  4. Pan, K.M. et al. Conversion of α-helices into β-sheets features in the formation of the scrapie prion proteins. Proc. Natl. Acad. Sci. USA 90, 10962–10966 (1993).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  6. Büeler, H. et al. Mice devoid of PrP are resistant to scrapie. Cell 73, 1339–1347 (1993).

    Article  Google Scholar 

  7. Xi, Y.G., Ingrosso, L., Ladogana, A., Masullo, C. & Pocchiari, M. Amphotericin B treatment dissociates in vivo replication of the scrapie agent from PrP accumulation. Nature 356, 598–601 (1992).

    Article  CAS  Google Scholar 

  8. Prusiner, S.B. Inherited prion diseases. Proc. Natl. Acad. Sci. USA 91, 4611–4614 (1994).

    Article  CAS  Google Scholar 

  9. Mastrianni, J.A. Lannicola, C. Myers, R.M. DeArmond, S. & Prusiner, S.B. Mutation of the prion protein gene at codon 208 in familial Creutzfeldt-Jakob disease. Neurology 47, 1305–1312 (1996).

    Article  CAS  Google Scholar 

  10. Goldfarb, L.G. & Brown, P. The transmissible spongiform encephalopathies. Annu. Rev. Med. 46, 57–65 (1995).

    Article  CAS  Google Scholar 

  11. Masullo, C., Salvatore, M., Macchi, G., Genuardi, M. & Pocchiari, M. Progressive dementia in a young patient with a homozygous deletion of the PrP gene. Ann. N. Y. Acad. Sci. 724, 358–360 (1994).

    Article  CAS  Google Scholar 

  12. Salvatore, M. et al. Polymorphisms of the prion protein gene in Italian patients with Creutzfeldt-Jakob disease. Hum. Genet. 94, 375–379 (1994).

    Article  CAS  Google Scholar 

  13. 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  Google Scholar 

  14. Tateishi, J. et al. First experimental transmission of fatal familial insomnia. Nature 376, 434–435 (1995).

    Article  CAS  Google Scholar 

  15. Windl, O. et al. Genetic basis of Creutzfeldt-Jakob disease in the United Kingdom: A systematic analysis of predisposing mutations and allelic variation in the PRNP gene. Hum. Genet. 98, 259–264 (1996).

    Article  CAS  Google Scholar 

  16. Goldfarb, L.G. et al. Fatal familial insomnia and familial Creutzfeldt-Jakob disease: Disease phenotype determined by a DNA polymorphism. Science 258, 806–808 (1992).

    Article  CAS  Google Scholar 

  17. Pocchiari, M. et al. A new point mutation of the prion protein gene in Creutzfeldt-Jakob disease. Ann. Neurol. 34, 802–807 (1993).

    Article  CAS  Google Scholar 

  18. Barbanti, P. et al. Polymorphism at codon 129 or codon 219 of PRNP and clinical heterogeneity in a previously unreported family with Gerstmann-Strässler-Scheinker disease (PrP-P102L mutation). Neurology 47, 734–741 (1996).

    Article  CAS  Google Scholar 

  19. Furukawa, H., Kitamoto, T., Tanaka, Y. & Tateishi, J. New variant prion protein in a Japanese family with Gerstmann-Sträusler syndrome. Mol. Brain Res. 30, 385–388 (1995).

    Article  CAS  Google Scholar 

  20. Petraroli, R. & Pocchiari, M. Codon 219 polymorphism of PRNP in healthy Caucasians and Creutzfeldt-Jakob disease patients. Am. J. Hum. Genet. 58, 888–889 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Prusiner, S.B. Biology and genetics of prion diseases. Annu. Rev. Microbiol. 48, 655–686 (1994).

    Article  CAS  Google Scholar 

  22. Weissmann, C. Molecular biology of transmissible spongiform encephalopathies. FEBS Lett. 389, 3–11 (1996).

    Article  CAS  Google Scholar 

  23. 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  Google Scholar 

  24. Weissmann, C. A ‘unified theory’ of prion propagation. Nature 352, 679–683 (1991).

    Article  CAS  Google Scholar 

  25. Diringer, H., Beekes, M. & Oberdieck, U. The nature of the scrapie agent: The virus theory. Ann. N. Y. Acad. Sci. 724, 246–258 (1994).

    Article  CAS  Google Scholar 

  26. Kitamoto, T., Yamaguchi, K., Doh-ura, K. & Tateishi, J.A. A prion protein missense variant is integrated in kuru plaque cores in patients with Gerstmann-Straussler syndrome. Neurology 41, 306–310 (1991).

    Article  CAS  Google Scholar 

  27. Tagliavini, F. et al. Amyloid fibrils in Gerstmann-Sträussler-Scheinker disease (Indiana and Swedish kindreds) express only PrP peptides encoded by the mutant allele. Cell 79, 695–703 (1994).

    Article  CAS  Google Scholar 

  28. Gabizon, R. et al. Insoluble wild-type and protease-resistant mutant prion protein in brains of patients with inherited prion disease. Nature Med. 2, 59–64 (1996).

    Article  CAS  Google Scholar 

  29. Ghetti, B. et al. Vascular variant of prion protein cerebral amyloidosis with T-positive neurofibrillary tangles: The phenotype of the stop codon 145 mutation in PRNP. Proc. Natl. Acad. Sci. USA 93, 744–748 (1996).

    Article  CAS  Google Scholar 

  30. Prelli, F. et al. Expression of a normal and variant Alzheimer's β-protein gene in amyloid of hereditary cerebral hemorrhage, Dutch type: DNA and protein diagnostic assays. Biochem. Biophys. Res. Commun. 170, 301–307 (1990).

    Article  CAS  Google Scholar 

  31. Tawara, S., Nakazato, M., Kangawa, K., Matsuo, H. & Araki, S. Identification of amyloid prealbumin in familial amyloidotic polyneuropathy (Japanese type). Biochem. Biophys. Res. Commun. 116, 880–888 (1983).

    Article  CAS  Google Scholar 

  32. Saraiva, M.J.M., Birken, S., Costa, P.P. & Goodman, D.S. Amyloid fibril protein in familial amyloidotic polyneuropathy, Portuguese type. J. Clin. Invest. 74, 104–119 (1984).

    Article  CAS  Google Scholar 

  33. Dwulet, F.E. & Benson, M.D. Primary structure of an amyloid prealbumin and its plasma precursor in a heredofamilial polyneuropathy of Swedish origin. Proc. Natl. Acad. Sci. USA 81, 694–698 (1984).

    Article  CAS  Google Scholar 

  34. Dwulet, F.E. & Benson, M.D. Characterization of a transthyretin (prealbumin) variant associated with familial amyloidotic polyneuropathy type II (Indiana/Swiss). J. Clin. Invest. 78, 880–886 (1986).

    Article  CAS  Google Scholar 

  35. Westermark, P., Sletten, K. & Olofsson, B.O. Prealbumin variants in the amyloid fibrils of Swedish familial amyloidotic polyneuropathy. Clin. Exp. Immunol. 69, 695–701 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Gajdusek, D.C. Spontaneous generation of infectious nucleating amyloids in the transmissible and nontransmissible cerebral amyloidoses. Mol. Neurobiol. 8, 1–13 (1994).

    Article  CAS  Google Scholar 

  37. Jarrett, J.T. & Lansbury, P.T. Jr. Seeding “one-dimensional crystallization” of amyloid: A pathogenic mechanism in Alzheimer's disease and scrapie? Cell 73, 1055–1058 (1993).

    Article  CAS  Google Scholar 

  38. Eaton, W.A. & Hofrichter, J. Sickle cell hemoglobin polymerization. Adv. Protein Chem. 40, 63–279 (1990).

    Article  CAS  Google Scholar 

  39. Goldfarb, L.G. et al. Synthetic peptides corresponding to different mutated regions of the amyloid gene in familial Creutzfeldt-Jakob disease show enhanced in vitro formation of morphologically different amyloid fibrils. Proc. Natl. Acad. Sci. USA 90, 4451–4454 (1993).

    Article  CAS  Google Scholar 

  40. Gasset, M. et al. Predicted alpha-helical regions of the prion protein when synthesized as peptides form amyloid. Proc. Natl. Acad. Sci. USA 89, 10940–10944 (1992).

    Article  CAS  Google Scholar 

  41. Riek, R. et al. NMR structure of the mouse prion protein domain PrP(121-231). Nature 382, 180–182 (1996).

    Article  CAS  Google Scholar 

  42. Brown, P. et al. latrogenic Creutzfeldt-jakob disease: An example of the interplay between ancient genes and modern medicine. Neurology 44, 291–293 (1994).

    Article  CAS  Google Scholar 

  43. Come, J.H., Fraser, P.E. & Lansbury, P.T. Jr. A kinetic model for amyloid formation in the prion diseases: Importance of seeding. Proc. Natl. Acad. Sci. USA 90, 5959–5963 (1993).

    Article  CAS  Google Scholar 

  44. Come, J.H. & Lansbury, P.T., Jr. Predisposition of prion protein homozygotes to Creutzfeldt-Jakob disease can be explained by a nucleation-dependent polymerization mechanism. J. Am. Chem. Sac. 116, 4109–4110 (1994).

    Article  CAS  Google Scholar 

  45. Manuelidis, L. & Fritch, W. Infectivity and host responses in Creutzfeldt-Jakob disease. Virology 216, 46–59 (1996).

    Article  CAS  Google Scholar 

  46. Xi, Y.G., Cardone, F. & Pocchiari, M. Detection of proteinase-resistant protein (PrP) in small brain tissue samples from Creutzfeldt-Jakob disease patients. J. Neurol. Sci. 124, 171–173 (1994).

    Article  CAS  Google Scholar 

  47. Kascsak, R.J. et al. Immunological comparison of scrapie-associated fibrils isolated from animals infected with four different scrapie strains. J. Virol. 59, 676–683 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Kretzschmar, H.A. et al. Molecular cloning of a human prion protein cDNA. DNA 5, 315–324 (1986).

    Article  CAS  Google Scholar 

Download references

Author information

Author notes

  1. Maria Chiara Silvestrini: Deceased, see Acknowledgements.

Authors and Affiliations

  1. Dipartimento di Scienze Biochimiche “A. Rossi Fanelli,” Universita di Roma “La Sapienza,” and Centra di Biologia Molecolare del Consiglio Nazionale delle Ricerche, Piazzale Aldo Moro 5, 00185, Rome, Italy

    Maria Chiara Silvestrini, Bruno Maras, Donatella Barra & Maurizio Brunori

  2. Laboratorio di Virologia, Istituto Superiors di Sanita, Viale Regina Elena 299, 00161, Rome, Italy

    Franco Cardone & Maurizio Pocchiari

  3. Dipartimento di Chimica Organica e Biologica, Università di Napoli “Federico II,”, 80134, Naples, Italy

    Piero Pucci

Authors
  1. Maria Chiara Silvestrini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Franco Cardone
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bruno Maras
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Piero Pucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Donatella Barra
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maurizio Brunori
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Maurizio Pocchiari
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Silvestrini, M., Cardone, F., Maras, B. et al. Identification of the prion protein allotypes which accumulate in the brain of sporadic and familial Creutzfeldt-Jakob disease patients. Nat Med 3, 521–525 (1997). https://doi.org/10.1038/nm0597-521

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0597-521

This article is cited by

Search

Advanced 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