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. 1995 Dec;69(12):7586–7592. doi: 10.1128/jvi.69.12.7586-7592.1995

Accumulation of proteinase K-resistant prion protein (PrP) is restricted by the expression level of normal PrP in mice inoculated with a mouse-adapted strain of the Creutzfeldt-Jakob disease agent.

S Sakaguchi 1, S Katamine 1, K Shigematsu 1, A Nakatani 1, R Moriuchi 1, N Nishida 1, K Kurokawa 1, R Nakaoke 1, H Sato 1, K Jishage 1, et al.
PMCID: PMC189697  PMID: 7494265

Abstract

Creutzfeldt-Jakob disease (CJD) is a transmissible neurodegenerative disease of humans caused by an unidentified infectious agent, the prion. To determine whether there was an involvement of the host-encoded prion protein (PrPc) in CJD development and prion propagation, mice heterozygous (PrP+/-) or homozygous (PrP-/-) for a disrupted PrP gene were established and inoculated with the mouse-adapted CJD agent. In keeping with findings of previous studies using other lines of PrP-less mice inoculated with scrapie agents, no PrP-/- mice showed any sign of the disease for 460 days after inoculation, while all of the PrP+/- and control PrP+/+ mice developed CJD-like symptoms and died. The incubation period for PrP+/- mice, 259 +/- 27 days, was much longer than that for PrP+/+ mice, 138 +/- 12 days. Propagation of the prion was barely detectable in the brains of PrP-/- mice and was estimated to be at a level at least 4 orders of magnitude lower than that in PrP+/+ mice. These findings indicate that PrPc is necessary for both the development of the disease and propagation of the prion in the inoculated mice. The proteinase-resistant PrP (PrPres) was undetectable in the brain tissues of the inoculated PrP-/- mice, while it accumulated in the affected brains of PrP+/+ and PrP+/- mice. Interestingly, the maximum level of PrPres in the brains of PrP+/- mice was about half of the level in the similarly affected brains of PrP+/+ mice, indicating that PrPres accumulation is restricted by the level of PrPc.

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Selected References

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  1. Alper T. Scrapie agent unlike viruses in size and susceptibility to inactivation by ionizing or ultraviolet radiation. Nature. 1985 Oct 24;317(6039):750–750. doi: 10.1038/317750a0. [DOI] [PubMed] [Google Scholar]
  2. Bendheim P. E., Bockman J. M., McKinley M. P., Kingsbury D. T., Prusiner S. B. Scrapie and Creutzfeldt-Jakob disease prion proteins share physical properties and antigenic determinants. Proc Natl Acad Sci U S A. 1985 Feb;82(4):997–1001. doi: 10.1073/pnas.82.4.997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bernoulli C., Siegfried J., Baumgartner G., Regli F., Rabinowicz T., Gajdusek D. C., Gibbs C. J., Jr Danger of accidental person-to-person transmission of Creutzfeldt-Jakob disease by surgery. Lancet. 1977 Feb 26;1(8009):478–479. doi: 10.1016/s0140-6736(77)91958-4. [DOI] [PubMed] [Google Scholar]
  4. Bolton D. C., McKinley M. P., Prusiner S. B. Identification of a protein that purifies with the scrapie prion. Science. 1982 Dec 24;218(4579):1309–1311. doi: 10.1126/science.6815801. [DOI] [PubMed] [Google Scholar]
  5. Brown P., Liberski P. P., Wolff A., Gajdusek D. C. Conservation of infectivity in purified fibrillary extracts of scrapie-infected hamster brain after sequential enzymatic digestion or polyacrylamide gel electrophoresis. Proc Natl Acad Sci U S A. 1990 Sep;87(18):7240–7244. doi: 10.1073/pnas.87.18.7240. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bruce M. E., Dickinson A. G. Biological evidence that scrapie agent has an independent genome. J Gen Virol. 1987 Jan;68(Pt 1):79–89. doi: 10.1099/0022-1317-68-1-79. [DOI] [PubMed] [Google Scholar]
  7. Büeler H., Aguzzi A., Sailer A., Greiner R. A., Autenried P., Aguet M., Weissmann C. Mice devoid of PrP are resistant to scrapie. Cell. 1993 Jul 2;73(7):1339–1347. doi: 10.1016/0092-8674(93)90360-3. [DOI] [PubMed] [Google Scholar]
  8. Büeler H., Fischer M., Lang Y., Bluethmann H., Lipp H. P., DeArmond S. J., Prusiner S. B., Aguet M., Weissmann C. Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature. 1992 Apr 16;356(6370):577–582. doi: 10.1038/356577a0. [DOI] [PubMed] [Google Scholar]
  9. Büeler H., Raeber A., Sailer A., Fischer M., Aguzzi A., Weissmann C. High prion and PrPSc levels but delayed onset of disease in scrapie-inoculated mice heterozygous for a disrupted PrP gene. Mol Med. 1994 Nov;1(1):19–30. [PMC free article] [PubMed] [Google Scholar]
  10. CHANDLER R. L. Encephalopathy in mice produced by inoculation with scrapie brain material. Lancet. 1961 Jun 24;1(7191):1378–1379. doi: 10.1016/s0140-6736(61)92008-6. [DOI] [PubMed] [Google Scholar]
  11. Chesebro B., Caughey B. Scrapie agent reflication without the prion protein? Curr Biol. 1993 Oct 1;3(10):696–698. doi: 10.1016/0960-9822(93)90072-v. [DOI] [PubMed] [Google Scholar]
  12. Collinge J., Whittington M. A., Sidle K. C., Smith C. J., Palmer M. S., Clarke A. R., Jefferys J. G. Prion protein is necessary for normal synaptic function. Nature. 1994 Jul 28;370(6487):295–297. doi: 10.1038/370295a0. [DOI] [PubMed] [Google Scholar]
  13. Duffy P., Wolf J., Collins G., DeVoe A. G., Streeten B., Cowen D. Letter: Possible person-to-person transmission of Creutzfeldt-Jakob disease. N Engl J Med. 1974 Mar 21;290(12):692–693. [PubMed] [Google Scholar]
  14. Forloni G., Angeretti N., Chiesa R., Monzani E., Salmona M., Bugiani O., Tagliavini F. Neurotoxicity of a prion protein fragment. Nature. 1993 Apr 8;362(6420):543–546. doi: 10.1038/362543a0. [DOI] [PubMed] [Google Scholar]
  15. Hsiao K. K., Scott M., Foster D., Groth D. F., DeArmond S. J., Prusiner S. B. Spontaneous neurodegeneration in transgenic mice with mutant prion protein. Science. 1990 Dec 14;250(4987):1587–1590. doi: 10.1126/science.1980379. [DOI] [PubMed] [Google Scholar]
  16. Kimberlin R. H., Walker C. A. Evidence that the transmission of one source of scrapie agent to hamsters involves separation of agent strains from a mixture. J Gen Virol. 1978 Jun;39(3):487–496. doi: 10.1099/0022-1317-39-3-487. [DOI] [PubMed] [Google Scholar]
  17. Kitamoto T., Muramoto T., Mohri S., Doh-Ura K., Tateishi J. Abnormal isoform of prion protein accumulates in follicular dendritic cells in mice with Creutzfeldt-Jakob disease. J Virol. 1991 Nov;65(11):6292–6295. doi: 10.1128/jvi.65.11.6292-6295.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Li E., Bestor T. H., Jaenisch R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell. 1992 Jun 12;69(6):915–926. doi: 10.1016/0092-8674(92)90611-f. [DOI] [PubMed] [Google Scholar]
  19. Manson J. C., Clarke A. R., Hooper M. L., Aitchison L., McConnell I., Hope J. 129/Ola mice carrying a null mutation in PrP that abolishes mRNA production are developmentally normal. Mol Neurobiol. 1994 Apr-Jun;8(2-3):121–127. doi: 10.1007/BF02780662. [DOI] [PubMed] [Google Scholar]
  20. Manson J. C., Clarke A. R., McBride P. A., McConnell I., Hope J. PrP gene dosage determines the timing but not the final intensity or distribution of lesions in scrapie pathology. Neurodegeneration. 1994 Dec;3(4):331–340. [PubMed] [Google Scholar]
  21. Manuelidis E. E., Angelo J. N., Gorgacz E. J., Manuelidis L. Transmission of Creutzfeldt-Jakob disease to Syrian hamster. Lancet. 1977 Feb 26;1(8009):479–479. doi: 10.1016/s0140-6736(77)91959-6. [DOI] [PubMed] [Google Scholar]
  22. McKinley M. P., Bolton D. C., Prusiner S. B. A protease-resistant protein is a structural component of the scrapie prion. Cell. 1983 Nov;35(1):57–62. doi: 10.1016/0092-8674(83)90207-6. [DOI] [PubMed] [Google Scholar]
  23. Medori R., Montagna P., Tritschler H. J., LeBlanc A., Cortelli P., Tinuper P., Lugaresi E., Gambetti P. Fatal familial insomnia: a second kindred with mutation of prion protein gene at codon 178. Neurology. 1992 Mar;42(3 Pt 1):669–670. doi: 10.1212/wnl.42.3.669. [DOI] [PubMed] [Google Scholar]
  24. Oesch B., Westaway D., Wälchli M., McKinley M. P., Kent S. B., Aebersold R., Barry R. A., Tempst P., Teplow D. B., Hood L. E. A cellular gene encodes scrapie PrP 27-30 protein. Cell. 1985 Apr;40(4):735–746. doi: 10.1016/0092-8674(85)90333-2. [DOI] [PubMed] [Google Scholar]
  25. Prusiner S. B., Groth D. F., Bolton D. C., Kent S. B., Hood L. E. Purification and structural studies of a major scrapie prion protein. Cell. 1984 Aug;38(1):127–134. doi: 10.1016/0092-8674(84)90533-6. [DOI] [PubMed] [Google Scholar]
  26. Prusiner S. B., Groth D., Serban A., Koehler R., Foster D., Torchia M., Burton D., Yang S. L., DeArmond S. J. Ablation of the prion protein (PrP) gene in mice prevents scrapie and facilitates production of anti-PrP antibodies. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10608–10612. doi: 10.1073/pnas.90.22.10608. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Prusiner S. B. Novel proteinaceous infectious particles cause scrapie. Science. 1982 Apr 9;216(4542):136–144. doi: 10.1126/science.6801762. [DOI] [PubMed] [Google Scholar]
  28. Rudnicki M. A., Braun T., Hinuma S., Jaenisch R. Inactivation of MyoD in mice leads to up-regulation of the myogenic HLH gene Myf-5 and results in apparently normal muscle development. Cell. 1992 Oct 30;71(3):383–390. doi: 10.1016/0092-8674(92)90508-a. [DOI] [PubMed] [Google Scholar]
  29. Sailer A., Büeler H., Fischer M., Aguzzi A., Weissmann C. No propagation of prions in mice devoid of PrP. Cell. 1994 Jul 1;77(7):967–968. doi: 10.1016/0092-8674(94)90436-7. [DOI] [PubMed] [Google Scholar]
  30. Sakaguchi S., Katamine S., Yamanouchi K., Kishikawa M., Moriuchi R., Yasukawa N., Doi T., Miyamoto T. Kinetics of infectivity are dissociated from PrP accumulation in salivary glands of Creutzfeldt-Jakob disease agent-inoculated mice. J Gen Virol. 1993 Oct;74(Pt 10):2117–2123. doi: 10.1099/0022-1317-74-10-2117. [DOI] [PubMed] [Google Scholar]
  31. Shinagawa M., Munekata E., Doi S., Takahashi K., Goto H., Sato G. Immunoreactivity of a synthetic pentadecapeptide corresponding to the N-terminal region of the scrapie prion protein. J Gen Virol. 1986 Aug;67(Pt 8):1745–1750. doi: 10.1099/0022-1317-67-8-1745. [DOI] [PubMed] [Google Scholar]
  32. Tateishi J., Ohta M., Koga M., Sato Y., Kuroiwa Y. Transmission of chronic spongiform encephalopathy with kuru plaques from humans to small rodents. Ann Neurol. 1979 Jun;5(6):581–584. doi: 10.1002/ana.410050616. [DOI] [PubMed] [Google Scholar]
  33. Weber T., Tumani H., Holdorff B., Collinge J., Palmer M., Kretzschmar H. A., Felgenhauer K. Transmission of Creutzfeldt-Jakob disease by handling of dura mater. Lancet. 1993 Jan 9;341(8837):123–124. doi: 10.1016/0140-6736(93)92608-v. [DOI] [PubMed] [Google Scholar]
  34. Weissmann C. A 'unified theory' of prion propagation. Nature. 1991 Aug 22;352(6337):679–683. doi: 10.1038/352679a0. [DOI] [PubMed] [Google Scholar]
  35. Westaway D., DeArmond S. J., Cayetano-Canlas J., Groth D., Foster D., Yang S. L., Torchia M., Carlson G. A., Prusiner S. B. Degeneration of skeletal muscle, peripheral nerves, and the central nervous system in transgenic mice overexpressing wild-type prion proteins. Cell. 1994 Jan 14;76(1):117–129. doi: 10.1016/0092-8674(94)90177-5. [DOI] [PubMed] [Google Scholar]
  36. Whittington M. A., Sidle K. C., Gowland I., Meads J., Hill A. F., Palmer M. S., Jefferys J. G., Collinge J. Rescue of neurophysiological phenotype seen in PrP null mice by transgene encoding human prion protein. Nat Genet. 1995 Feb;9(2):197–201. doi: 10.1038/ng0295-197. [DOI] [PubMed] [Google Scholar]
  37. 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. 1992 Apr 16;356(6370):598–601. doi: 10.1038/356598a0. [DOI] [PubMed] [Google Scholar]

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