Ablation of the prion protein (PrP) gene in mice prevents scrapie and facilitates production of anti-PrP antibodies (original) (raw)

Abstract

Mice, homozygous for prion protein (PrP) gene ablation (Prn-p0/0), develop normally and remain well > 500 days after inoculation with murine scrapie prions. In contrast, wild-type mice developed scrapie < 165 days after inoculation and most Prn-p0/+ mice, heterozygous for disruption of the PrP gene, exhibited signs of central nervous system dysfunction between 400 and 465 days after inoculation. In situ immunoblots showed widespread deposition of scrapie PrP (PrPSc) in the brains of both wild-type Prn-p+/+ and Prn-p0/+ mice, while neither cellular PrP (PrPC) nor PrPSc was detected in the brains of Prn-p0/0 mice. In contrast to Prn-p+/+ and Prn-p0/+ mice, Prn-p0/0 mice failed to propagate prion infectivity as measured by bioassays. Syrian hamster (SHa) PrP transgenes rendered Prn-p0/0 mice susceptible to prions containing SHaPrPSc. Immunization of Prn-p0/0 mice with purified, infectious mouse or SHa prions dispersed in Freund's adjuvant produced antisera that bound mouse, SHa, and human PrP on Western blots. Presumably, the lack of PrPC expression in Prn-p0/0 mice prevents them from becoming tolerant to the immunogen. The resistance of Prn-p0/0 mice to developing scrapie after inoculation with murine prions supports the hypothesis that PrPSc is essential for both transmission and pathogenesis of the prion diseases.

10608

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Barry R. A., Prusiner S. B. Monoclonal antibodies to the cellular and scrapie prion proteins. J Infect Dis. 1986 Sep;154(3):518–521. doi: 10.1093/infdis/154.3.518. [DOI] [PubMed] [Google Scholar]
  2. Bellinger-Kawahara C., Cleaver J. E., Diener T. O., Prusiner S. B. Purified scrapie prions resist inactivation by UV irradiation. J Virol. 1987 Jan;61(1):159–166. doi: 10.1128/jvi.61.1.159-166.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. 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]
  4. Bode L., Pocchiari M., Gelderblom H., Diringer H. Characterization of antisera against scrapie-associated fibrils (SAF) from affected hamster and cross-reactivity with SAF from scrapie-affected mice and from patients with Creutzfeldt-Jakob disease. J Gen Virol. 1985 Nov;66(Pt 11):2471–2478. doi: 10.1099/0022-1317-66-11-2471. [DOI] [PubMed] [Google Scholar]
  5. Bolton D. C., Seligman S. J., Bablanian G., Windsor D., Scala L. J., Kim K. S., Chen C. M., Kascsak R. J., Bendheim P. E. Molecular location of a species-specific epitope on the hamster scrapie agent protein. J Virol. 1991 Jul;65(7):3667–3675. doi: 10.1128/jvi.65.7.3667-3675.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Butler D. A., Scott M. R., Bockman J. M., Borchelt D. R., Taraboulos A., Hsiao K. K., Kingsbury D. T., Prusiner S. B. Scrapie-infected murine neuroblastoma cells produce protease-resistant prion proteins. J Virol. 1988 May;62(5):1558–1564. doi: 10.1128/jvi.62.5.1558-1564.1988. [DOI] [PMC free article] [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. 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]
  10. Carlson G. A., Kingsbury D. T., Goodman P. A., Coleman S., Marshall S. T., DeArmond S., Westaway D., Prusiner S. B. Linkage of prion protein and scrapie incubation time genes. Cell. 1986 Aug 15;46(4):503–511. doi: 10.1016/0092-8674(86)90875-5. [DOI] [PubMed] [Google Scholar]
  11. Casaccia-Bonnefil P., Kascsak R. J., Fersko R., Callahan S., Carp R. I. Brain regional distribution of prion protein PrP27-30 in mice stereotaxically microinjected with different strains of scrapie. J Infect Dis. 1993 Jan;167(1):7–12. doi: 10.1093/infdis/167.1.7. [DOI] [PubMed] [Google Scholar]
  12. Chesebro B., Race R., Wehrly K., Nishio J., Bloom M., Lechner D., Bergstrom S., Robbins K., Mayer L., Keith J. M. Identification of scrapie prion protein-specific mRNA in scrapie-infected and uninfected brain. Nature. 1985 May 23;315(6017):331–333. doi: 10.1038/315331a0. [DOI] [PubMed] [Google Scholar]
  13. Chesebro B. Spongiform encephalopathies. PrP and the scrapie agent. Nature. 1992 Apr 16;356(6370):560–560. doi: 10.1038/356560a0. [DOI] [PubMed] [Google Scholar]
  14. DeArmond S. J., Yang S. L., Lee A., Bowler R., Taraboulos A., Groth D., Prusiner S. B. Three scrapie prion isolates exhibit different accumulation patterns of the prion protein scrapie isoform. Proc Natl Acad Sci U S A. 1993 Jul 15;90(14):6449–6453. doi: 10.1073/pnas.90.14.6449. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Diringer H., Ehlers B. Chemoprophylaxis of scrapie in mice. J Gen Virol. 1991 Feb;72(Pt 2):457–460. doi: 10.1099/0022-1317-72-2-457. [DOI] [PubMed] [Google Scholar]
  16. Eklund C. M., Kennedy R. C., Hadlow W. J. Pathogenesis of scrapie virus infection in the mouse. J Infect Dis. 1967 Feb;117(1):15–22. doi: 10.1093/infdis/117.1.15. [DOI] [PubMed] [Google Scholar]
  17. Gabizon R., Prusiner S. B. Prion liposomes. Biochem J. 1990 Feb 15;266(1):1–14. doi: 10.1042/bj2660001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Gardner M. B., Henderson B. E., Officer J. E., Rongey R. W., Parker J. C., Oliver C., Estes J. D., Huebner R. J. A spontaneous lower motor neuron disease apparently caused by indigenous type-C RNA virus in wild mice. J Natl Cancer Inst. 1973 Oct;51(4):1243–1254. doi: 10.1093/jnci/51.4.1243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Gasset M., Baldwin M. A., Lloyd D. H., Gabriel J. M., Holtzman D. M., Cohen F., Fletterick R., Prusiner S. B. Predicted alpha-helical regions of the prion protein when synthesized as peptides form amyloid. Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10940–10944. doi: 10.1073/pnas.89.22.10940. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hecker R., Taraboulos A., Scott M., Pan K. M., Yang S. L., Torchia M., Jendroska K., DeArmond S. J., Prusiner S. B. Replication of distinct scrapie prion isolates is region specific in brains of transgenic mice and hamsters. Genes Dev. 1992 Jul;6(7):1213–1228. doi: 10.1101/gad.6.7.1213. [DOI] [PubMed] [Google Scholar]
  21. Kascsak R. J., Rubenstein R., Merz P. A., Tonna-DeMasi M., Fersko R., Carp R. I., Wisniewski H. M., Diringer H. Mouse polyclonal and monoclonal antibody to scrapie-associated fibril proteins. J Virol. 1987 Dec;61(12):3688–3693. doi: 10.1128/jvi.61.12.3688-3693.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kimberlin R. H., Walker C. A., Fraser H. The genomic identity of different strains of mouse scrapie is expressed in hamsters and preserved on reisolation in mice. J Gen Virol. 1989 Aug;70(Pt 8):2017–2025. doi: 10.1099/0022-1317-70-8-2017. [DOI] [PubMed] [Google Scholar]
  23. Kimberlin R. H., Walker C. Characteristics of a short incubation model of scrapie in the golden hamster. J Gen Virol. 1977 Feb;34(2):295–304. doi: 10.1099/0022-1317-34-2-295. [DOI] [PubMed] [Google Scholar]
  24. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  25. Marsh R. F., Kimberlin R. H. Comparison of scrapie and transmissible mink encephalopathy in hamsters. II. Clinical signs, pathology, and pathogenesis. J Infect Dis. 1975 Feb;131(2):104–110. doi: 10.1093/infdis/131.2.104. [DOI] [PubMed] [Google Scholar]
  26. McMahon A. P., Bradley A. The Wnt-1 (int-1) proto-oncogene is required for development of a large region of the mouse brain. Cell. 1990 Sep 21;62(6):1073–1085. doi: 10.1016/0092-8674(90)90385-r. [DOI] [PubMed] [Google Scholar]
  27. 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]
  28. PARRY H. B. Scrapie: a transmissible and hereditary disease of sheep. Heredity (Edinb) 1962 Feb;17:75–105. doi: 10.1038/hdy.1962.4. [DOI] [PubMed] [Google Scholar]
  29. Prusiner S. B., Bolton D. C., Groth D. F., Bowman K. A., Cochran S. P., McKinley M. P. Further purification and characterization of scrapie prions. Biochemistry. 1982 Dec 21;21(26):6942–6950. doi: 10.1021/bi00269a050. [DOI] [PubMed] [Google Scholar]
  30. Prusiner S. B., Garfin D. E., Cochran S. P., McKinley M. P., Groth D. F., Hadlow W. J., Race R. E., Eklund C. M. Experimental scrapie in the mouse: electrophoretic and sedimentation properties of the partially purified agent. J Neurochem. 1980 Sep;35(3):574–582. doi: 10.1111/j.1471-4159.1980.tb03693.x. [DOI] [PubMed] [Google Scholar]
  31. 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]
  32. Prusiner S. B., Hadlow W. J., Garfin D. E., Cochran S. P., Baringer J. R., Race R. E., Eklund C. M. Partial purification and evidence for multiple molecular forms of the scrapie agent. Biochemistry. 1978 Nov 14;17(23):4993–4999. doi: 10.1021/bi00616a021. [DOI] [PubMed] [Google Scholar]
  33. Prusiner S. B., McKinley M. P., Bowman K. A., Bolton D. C., Bendheim P. E., Groth D. F., Glenner G. G. Scrapie prions aggregate to form amyloid-like birefringent rods. Cell. 1983 Dec;35(2 Pt 1):349–358. doi: 10.1016/0092-8674(83)90168-x. [DOI] [PubMed] [Google Scholar]
  34. Prusiner S. B. Molecular biology of prion diseases. Science. 1991 Jun 14;252(5012):1515–1522. doi: 10.1126/science.1675487. [DOI] [PubMed] [Google Scholar]
  35. Prusiner S. B., Scott M., Foster D., Pan K. M., Groth D., Mirenda C., Torchia M., Yang S. L., Serban D., Carlson G. A. Transgenetic studies implicate interactions between homologous PrP isoforms in scrapie prion replication. Cell. 1990 Nov 16;63(4):673–686. doi: 10.1016/0092-8674(90)90134-z. [DOI] [PubMed] [Google Scholar]
  36. Prusiner S. B. Scrapie prions. Annu Rev Microbiol. 1989;43:345–374. doi: 10.1146/annurev.mi.43.100189.002021. [DOI] [PubMed] [Google Scholar]
  37. Rogers M., Serban D., Gyuris T., Scott M., Torchia T., Prusiner S. B. Epitope mapping of the Syrian hamster prion protein utilizing chimeric and mutant genes in a vaccinia virus expression system. J Immunol. 1991 Nov 15;147(10):3568–3574. [PubMed] [Google Scholar]
  38. Scott M., Foster D., Mirenda C., Serban D., Coufal F., Wälchli M., Torchia M., Groth D., Carlson G., DeArmond S. J. Transgenic mice expressing hamster prion protein produce species-specific scrapie infectivity and amyloid plaques. Cell. 1989 Dec 1;59(5):847–857. doi: 10.1016/0092-8674(89)90608-9. [DOI] [PubMed] [Google Scholar]
  39. Scott M., Groth D., Foster D., Torchia M., Yang S. L., DeArmond S. J., Prusiner S. B. Propagation of prions with artificial properties in transgenic mice expressing chimeric PrP genes. Cell. 1993 Jun 4;73(5):979–988. doi: 10.1016/0092-8674(93)90275-u. [DOI] [PubMed] [Google Scholar]
  40. Serban D., Taraboulos A., DeArmond S. J., Prusiner S. B. Rapid detection of Creutzfeldt-Jakob disease and scrapie prion proteins. Neurology. 1990 Jan;40(1):110–117. doi: 10.1212/wnl.40.1.110. [DOI] [PubMed] [Google Scholar]
  41. Sharpe A. H., Hunter J. J., Chassler P., Jaenisch R. Role of abortive retroviral infection of neurons in spongiform CNS degeneration. Nature. 1990 Jul 12;346(6280):181–183. doi: 10.1038/346181a0. [DOI] [PubMed] [Google Scholar]
  42. Sklaviadis T., Dreyer R., Manuelidis L. Analysis of Creutzfeldt-Jakob disease infectious fractions by gel permeation chromatography and sedimentation field flow fractionation. Virus Res. 1992 Dec;26(3):241–254. doi: 10.1016/0168-1702(92)90016-3. [DOI] [PubMed] [Google Scholar]
  43. Taraboulos A., Jendroska K., Serban D., Yang S. L., DeArmond S. J., Prusiner S. B. Regional mapping of prion proteins in brain. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7620–7624. doi: 10.1073/pnas.89.16.7620. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Westaway D., Mirenda C. A., Foster D., Zebarjadian Y., Scott M., Torchia M., Yang S. L., Serban H., DeArmond S. J., Ebeling C. Paradoxical shortening of scrapie incubation times by expression of prion protein transgenes derived from long incubation period mice. Neuron. 1991 Jul;7(1):59–68. doi: 10.1016/0896-6273(91)90074-a. [DOI] [PubMed] [Google Scholar]
  45. Wilesmith J. W., Wells G. A. Bovine spongiform encephalopathy. Curr Top Microbiol Immunol. 1991;172:21–38. doi: 10.1007/978-3-642-76540-7_2. [DOI] [PubMed] [Google Scholar]
  46. 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]