Skip to main content
PMC home page
The EMBO Journal logoLink to The EMBO Journal
. 1997 Oct 15;16(20):6057–6065. doi: 10.1093/emboj/16.20.6057

Astrocyte-specific expression of hamster prion protein (PrP) renders PrP knockout mice susceptible to hamster scrapie.

A J Raeber 1, R E Race 1, S Brandner 1, S A Priola 1, A Sailer 1, R A Bessen 1, L Mucke 1, J Manson 1, A Aguzzi 1, M B Oldstone 1, C Weissmann 1, B Chesebro 1
PMCID: PMC1326289  PMID: 9321385

Abstract

Transmissible spongiform encephalopathies are characterized by spongiosis, astrocytosis and accumulation of PrPSc, an isoform of the normal host protein PrPC. The exact cell types responsible for agent propagation and pathogenesis are still uncertain. To determine the possible role of astrocytes, we generated mice devoid of murine PrP but expressing hamster PrP transgenes driven by the astrocyte-specific GFAP promoter. After inoculation with hamster scrapie, these mice accumulated infectivity and PrPSc to high levels, developed severe disease after 227 +/- 5 days and died 7 +/- 4 days later. Therefore, astrocytes could play an important role in scrapie pathogenesis, possibly by an indirect toxic effect on neurons. Interestingly, mice expressing the same transgenes but also endogenous murine PrP genes propagated infectivity without developing disease.

Full Text

The Full Text of this article is available as a PDF (549.3 KB).

Selected References

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

  1. Basler K., Oesch B., Scott M., Westaway D., Wälchli M., Groth D. F., McKinley M. P., Prusiner S. B., Weissmann C. Scrapie and cellular PrP isoforms are encoded by the same chromosomal gene. Cell. 1986 Aug 1;46(3):417–428. doi: 10.1016/0092-8674(86)90662-8. [DOI] [PubMed] [Google Scholar]
  2. 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]
  3. Brandner S., Isenmann S., Raeber A., Fischer M., Sailer A., Kobayashi Y., Marino S., Weissmann C., Aguzzi A. Normal host prion protein necessary for scrapie-induced neurotoxicity. Nature. 1996 Jan 25;379(6563):339–343. doi: 10.1038/379339a0. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. 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]
  6. 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]
  7. 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]
  8. Campbell I. L., Eddleston M., Kemper P., Oldstone M. B., Hobbs M. V. Activation of cerebral cytokine gene expression and its correlation with onset of reactive astrocyte and acute-phase response gene expression in scrapie. J Virol. 1994 Apr;68(4):2383–2387. doi: 10.1128/jvi.68.4.2383-2387.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cashman N. R., Loertscher R., Nalbantoglu J., Shaw I., Kascsak R. J., Bolton D. C., Bendheim P. E. Cellular isoform of the scrapie agent protein participates in lymphocyte activation. Cell. 1990 Apr 6;61(1):185–192. doi: 10.1016/0092-8674(90)90225-4. [DOI] [PubMed] [Google Scholar]
  10. Caughey B. W., Dong A., Bhat K. S., Ernst D., Hayes S. F., Caughey W. S. Secondary structure analysis of the scrapie-associated protein PrP 27-30 in water by infrared spectroscopy. Biochemistry. 1991 Aug 6;30(31):7672–7680. doi: 10.1021/bi00245a003. [DOI] [PubMed] [Google Scholar]
  11. Caughey B., Chesebro B. Prion protein and the transmissible spongiform encephalopathies. Trends Cell Biol. 1997 Feb;7(2):56–62. doi: 10.1016/S0962-8924(96)10054-4. [DOI] [PubMed] [Google Scholar]
  12. Caughey B., Race R. E., Chesebro B. Detection of prion protein mRNA in normal and scrapie-infected tissues and cell lines. J Gen Virol. 1988 Mar;69(Pt 3):711–716. doi: 10.1099/0022-1317-69-3-711. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  15. Collinge J., Palmer M. S., Sidle K. C., Gowland I., Medori R., Ironside J., Lantos P. Transmission of fatal familial insomnia to laboratory animals. Lancet. 1995 Aug 26;346(8974):569–570. doi: 10.1016/s0140-6736(95)91405-6. [DOI] [PubMed] [Google Scholar]
  16. Diedrich J. F., Bendheim P. E., Kim Y. S., Carp R. I., Haase A. T. Scrapie-associated prion protein accumulates in astrocytes during scrapie infection. Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):375–379. doi: 10.1073/pnas.88.2.375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. 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]
  18. Fischer M., Rülicke T., Raeber A., Sailer A., Moser M., Oesch B., Brandner S., Aguzzi A., Weissmann C. Prion protein (PrP) with amino-proximal deletions restoring susceptibility of PrP knockout mice to scrapie. EMBO J. 1996 Mar 15;15(6):1255–1264. [PMC free article] [PubMed] [Google Scholar]
  19. Fort P., Marty L., Piechaczyk M., el Sabrouty S., Dani C., Jeanteur P., Blanchard J. M. Various rat adult tissues express only one major mRNA species from the glyceraldehyde-3-phosphate-dehydrogenase multigenic family. Nucleic Acids Res. 1985 Mar 11;13(5):1431–1442. doi: 10.1093/nar/13.5.1431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Jeffrey M., Goodsir C. M., Bruce M., McBride P. A., Scott J. R., Halliday W. G. Correlative light and electron microscopy studies of PrP localisation in 87V scrapie. Brain Res. 1994 Sep 12;656(2):329–343. doi: 10.1016/0006-8993(94)91477-x. [DOI] [PubMed] [Google Scholar]
  21. Johnson W. B., Ruppe M. D., Rockenstein E. M., Price J., Sarthy V. P., Verderber L. C., Mucke L. Indicator expression directed by regulatory sequences of the glial fibrillary acidic protein (GFAP) gene: in vivo comparison of distinct GFAP-lacZ transgenes. Glia. 1995 Mar;13(3):174–184. doi: 10.1002/glia.440130304. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Kellings K., Meyer N., Mirenda C., Prusiner S. B., Riesner D. Analysis of nucleic acids in purified scrapie prion preparations. Arch Virol Suppl. 1993;7:215–225. doi: 10.1007/978-3-7091-9300-6_17. [DOI] [PubMed] [Google Scholar]
  24. 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]
  25. 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]
  26. Kretzschmar H. A., Prusiner S. B., Stowring L. E., DeArmond S. J. Scrapie prion proteins are synthesized in neurons. Am J Pathol. 1986 Jan;122(1):1–5. [PMC free article] [PubMed] [Google Scholar]
  27. Lynch W. P., Czub S., McAtee F. J., Hayes S. F., Portis J. L. Murine retrovirus-induced spongiform encephalopathy: productive infection of microglia and cerebellar neurons in accelerated CNS disease. Neuron. 1991 Sep;7(3):365–379. doi: 10.1016/0896-6273(91)90289-c. [DOI] [PubMed] [Google Scholar]
  28. 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]
  29. 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]
  30. McBride P. A., Eikelenboom P., Kraal G., Fraser H., Bruce M. E. PrP protein is associated with follicular dendritic cells of spleens and lymph nodes in uninfected and scrapie-infected mice. J Pathol. 1992 Dec;168(4):413–418. doi: 10.1002/path.1711680412. [DOI] [PubMed] [Google Scholar]
  31. Moser M., Colello R. J., Pott U., Oesch B. Developmental expression of the prion protein gene in glial cells. Neuron. 1995 Mar;14(3):509–517. doi: 10.1016/0896-6273(95)90307-0. [DOI] [PubMed] [Google Scholar]
  32. Mucke L., Eddleston M. Astrocytes in infectious and immune-mediated diseases of the central nervous system. FASEB J. 1993 Oct;7(13):1226–1232. doi: 10.1096/fasebj.7.13.8405808. [DOI] [PubMed] [Google Scholar]
  33. Mucke L., Oldstone M. B., Morris J. C., Nerenberg M. I. Rapid activation of astrocyte-specific expression of GFAP-lacZ transgene by focal injury. New Biol. 1991 May;3(5):465–474. [PubMed] [Google Scholar]
  34. 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]
  35. Pan K. M., Baldwin M., Nguyen J., Gasset M., Serban A., Groth D., Mehlhorn I., Huang Z., Fletterick R. J., Cohen F. E. Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):10962–10966. doi: 10.1073/pnas.90.23.10962. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Phillips M. J., Weller R. O., Kida S., Iannotti F. Focal brain damage enhances experimental allergic encephalomyelitis in brain and spinal cord. Neuropathol Appl Neurobiol. 1995 Jun;21(3):189–200. doi: 10.1111/j.1365-2990.1995.tb01050.x. [DOI] [PubMed] [Google Scholar]
  37. Pocchiari M. Prions and related neurological diseases. Mol Aspects Med. 1994;15(3):195–291. doi: 10.1016/0098-2997(94)90042-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Priola S. A., Caughey B., Race R. E., Chesebro B. Heterologous PrP molecules interfere with accumulation of protease-resistant PrP in scrapie-infected murine neuroblastoma cells. J Virol. 1994 Aug;68(8):4873–4878. doi: 10.1128/jvi.68.8.4873-4878.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Priola S. A., Chesebro B. A single hamster PrP amino acid blocks conversion to protease-resistant PrP in scrapie-infected mouse neuroblastoma cells. J Virol. 1995 Dec;69(12):7754–7758. doi: 10.1128/jvi.69.12.7754-7758.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. 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]
  41. Prusiner S. B. Human prion diseases and neurodegeneration. Curr Top Microbiol Immunol. 1996;207:1–17. doi: 10.1007/978-3-642-60983-1_1. [DOI] [PubMed] [Google Scholar]
  42. 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]
  43. 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]
  44. 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]
  45. Prusiner S. B. Scrapie prions. Annu Rev Microbiol. 1989;43:345–374. doi: 10.1146/annurev.mi.43.100189.002021. [DOI] [PubMed] [Google Scholar]
  46. Prusiner S. B. Transgenetic investigations of prion diseases of humans and animals. Philos Trans R Soc Lond B Biol Sci. 1993 Feb 27;339(1288):239–254. doi: 10.1098/rstb.1993.0022. [DOI] [PubMed] [Google Scholar]
  47. Race R. E., Priola S. A., Bessen R. A., Ernst D., Dockter J., Rall G. F., Mucke L., Chesebro B., Oldstone M. B. Neuron-specific expression of a hamster prion protein minigene in transgenic mice induces susceptibility to hamster scrapie agent. Neuron. 1995 Nov;15(5):1183–1191. doi: 10.1016/0896-6273(95)90105-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Robakis N. K., Sawh P. R., Wolfe G. C., Rubenstein R., Carp R. I., Innis M. A. Isolation of a cDNA clone encoding the leader peptide of prion protein and expression of the homologous gene in various tissues. Proc Natl Acad Sci U S A. 1986 Sep;83(17):6377–6381. doi: 10.1073/pnas.83.17.6377. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. 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]
  50. Scott J. R., Fraser H. Degenerative hippocampal pathology in mice infected with scrapie. Acta Neuropathol. 1984;65(1):62–68. doi: 10.1007/BF00689829. [DOI] [PubMed] [Google Scholar]
  51. Scott M. R., Köhler R., Foster D., Prusiner S. B. Chimeric prion protein expression in cultured cells and transgenic mice. Protein Sci. 1992 Aug;1(8):986–997. doi: 10.1002/pro.5560010804. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. 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]
  53. Stahl N., Borchelt D. R., Hsiao K., Prusiner S. B. Scrapie prion protein contains a phosphatidylinositol glycolipid. Cell. 1987 Oct 23;51(2):229–240. doi: 10.1016/0092-8674(87)90150-4. [DOI] [PubMed] [Google Scholar]
  54. Telling G. C., Haga T., Torchia M., Tremblay P., DeArmond S. J., Prusiner S. B. Interactions between wild-type and mutant prion proteins modulate neurodegeneration in transgenic mice. Genes Dev. 1996 Jul 15;10(14):1736–1750. doi: 10.1101/gad.10.14.1736. [DOI] [PubMed] [Google Scholar]
  55. Will R. G., Ironside J. W., Zeidler M., Cousens S. N., Estibeiro K., Alperovitch A., Poser S., Pocchiari M., Hofman A., Smith P. G. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet. 1996 Apr 6;347(9006):921–925. doi: 10.1016/s0140-6736(96)91412-9. [DOI] [PubMed] [Google Scholar]
  56. Williams A. E., van Dam A. M., Man-A-Hing W. K., Berkenbosch F., Eikelenboom P., Fraser H. Cytokines, prostaglandins and lipocortin-1 are present in the brains of scrapie-infected mice. Brain Res. 1994 Aug 22;654(2):200–206. doi: 10.1016/0006-8993(94)90480-4. [DOI] [PubMed] [Google Scholar]
  57. van Keulen L. J., Schreuder B. E., Meloen R. H., Poelen-van den Berg M., Mooij-Harkes G., Vromans M. E., Langeveld J. P. Immunohistochemical detection and localization of prion protein in brain tissue of sheep with natural scrapie. Vet Pathol. 1995 May;32(3):299–308. doi: 10.1177/030098589503200312. [DOI] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES