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:

Rescue of neurophysiological phenotype seen in PrP null mice by transgene encoding human prion protein

A Correction to this article was published on 01 April 1995

Abstract

The prion protein (PrP) is central to the aetiology of the prion diseases, transmissible neurodegenerative conditions of humans and animals. PrP null mice show abnormalities of synaptic neurophysiology, in particular weakened GABAA receptor–mediated fast inhibition and impaired long–term potentiation in the hippocampus. Here we demonstrate that this PrP null phenotype is rescued in mice with a high copy number of a transgene encoding human PrP but not in low copy number mice, confirming the specificity of the phenotype for loss of function of PrP. The ability of human PrP to compensate for loss of murine PrP will allow direct study of the functional consequences of the 18 human PrP mutations, which cause the inherited prion diseases; this phenotype can now form the basis of the first functional assay for PrP.

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

Similar content being viewed by others

References

  1. Weller, R.O. latrogenic transmission of Creutzfeldt-Jakob disease. Psychol. Med. 19, 1–4 (1989).

    Article  CAS  PubMed  Google Scholar 

  2. Prusiner, S.B., Biology of Priori Diseases. Science 252, 1515–1522 (1991).

    Article  CAS  PubMed  Google Scholar 

  3. Borchelt, D.R., Scott, M., Taraboulos, A., Stahl, N. & Prusiner, S.B. Scraple and cellular prion proteins differ in their kinetics of synthesis and topology in cultured cells. J Cell Biol. 110, 743–752 (1990).

    Article  CAS  PubMed  Google Scholar 

  4. Gasset, M., Baldwin, M.A., Fletterick, R.J. & Prusiner, S.B. Perturbation of the secondary structure of the scrapie prion protein under conditions that alter Infectivity. Proc. natn. Acad. Sci. U.S.A. 90, 1–5 (1993).

    Article  CAS  Google Scholar 

  5. Pan, K. et al. Conversion of α-helices into β-sheets features in the formation of the scrapie prion proteins. Proc natn. Acad Sci U.S.A., 90, 10962–10966 (1993).

    Article  CAS  Google Scholar 

  6. Prusiner, S.B. et al. Transgenetic studies Implicate Interactions between homologous PrP isoforms in scrapie prion replication. Cell 63, 673–686 (1990).

    Article  CAS  PubMed  Google Scholar 

  7. Weissmann, C. Spongiform encephalopathies. The prior's progress. Nature 349, 569–571 (1991).

    Article  CAS  PubMed  Google Scholar 

  8. 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 

  9. Baker, H.F. et al. Amino acid polymorphism in human prion protein and age at death In Inherited prion disease. Lancet 337, 1286 (1991).

    Article  CAS  PubMed  Google Scholar 

  10. Collinge, J., Palmer, M.S. & Dryden, A.J., Predisposition to latrogenic Creutzfeldt-Jakob disease. Lancet 337, 1441–1442 (1991).

    Article  CAS  PubMed  Google Scholar 

  11. Kocisko, D.A. et al. Cell-free formation of protease-resistant prion protein. Nature 370, 471–474 (1994).

    Article  CAS  PubMed  Google Scholar 

  12. Stahl, N., Borchelt, D.R. & Prusiner, S.B. Differential release of cellular and scrapie prion proteins from cellular membranes by phosphatldylinositol-specific phosphollpase. Biochemistry 29, 5405–5412 (1990).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  14. Westaway, D. & Prusiner, S.B. Conservation of the cellular gene encoding the scrapie prion protein. Nuci. Acids. Res. 14, 2035–2044 (1986).

    Article  CAS  Google Scholar 

  15. Harris, D.A., Falls, D.L., Johnson, F.A. & Fishbach, G.S. A prion-like protein from chicken brain copurifles with an acetylcholine receptor-inducing activity. Proc. natn. Acad. Sci. U.S.A. 88, 7664–7668 (1991).

    Article  CAS  Google Scholar 

  16. Harris, D.A., Lele, P. & Snider, W.D. Localization of the mRNA for a chicken prion protein by in situ hybridization. Proc. natn. Acad. Sci. U.S.A. 90, 4309–4313 (1993).

    Article  CAS  Google Scholar 

  17. Gabriel, J., Oesch, B., Kretzschmar, H., Scott, M. & Prusiner, S.B. Molecular cloning and structural analysis of a candidate chicken prion protein. In Prion Diseases of Humans and Animals (eds Prusiner, S.B., Collinge, J., Powell, J. & Anderton, B.) (Ellis Horwood, London, 1992).

    Google Scholar 

  18. Brenner, H.R., Herczeg, A. & Oesch, B. Normal development of nerve-muscle synapses In mice lacking the prion protein gene. Proc. R. Soc. Lond. Biol. 250, 151–155 (1992).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  20. Manson, J. et al. The prion protein gene: a role In mouse embryogenesis? Development 115, 117–122 (1992).

    CAS  PubMed  Google Scholar 

  21. Collinge, J. et al. Prion protein is necessary for normal synaptic function. Nature 370, 295–297 (1994).

    Article  CAS  PubMed  Google Scholar 

  22. Clinton, J., Forsyth, C., Royston, M.C. & Roberts, G.W. Synaptic degeneration is the primary neuropathological feature in prion disease: a preliminary study. Neuronport 4, 65–68 (1993).

    CAS  Google Scholar 

  23. Kascsak, R.J. et al. Mouse polyclonal and monoclonal antibody to scrapie-assoclated fibril proteins. J. Virol. 61, 3688–3693 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Telling, G.C. et al. Transmission of Creutzfeldt-Jakob disease from humans to transgenic mice expressing chimeric human-mouse prion protein. Proc natn. Acad Sci U.S.A. 91, 9936–9940 (1994).

    Article  CAS  Google Scholar 

  25. Hsiao, K. et al. Linkage of a prion protein missense variant to Gerstmann-Straussler syndrome. Nature 338, 342–345 (1989).

    Article  CAS  PubMed  Google Scholar 

  26. Collinge, J. & Palmer, M.S. & Prusiner, S.B. Prion diseases. Curr. Opin. Genet. Dev. 2, 448–453 (1992).

    Article  CAS  PubMed  Google Scholar 

  27. Jefferys, J.G.R., Empson, R.M., Whittington, M.A. & Prusiner, S.B. Infection of transgenic mice leads to network and intrinsic dysfunction of cortical and hippocampal neurons. Neurobiol. of Dis. 1, 3–15 (1994).

    Article  Google Scholar 

  28. Cathala, F. & Baron, H. Clinical aspects of Creutzfeldt-Jakob Disease. In Prions: Novel Infectious Pathogens Causing Scrapfe and Creutzfeldt-Jakob Disease (eds Prusiner, S.B. & McKinley, M.P.) 467–509 (Academic, California, (1987).

    Google Scholar 

  29. Collinge, J. et al. Prion dementia without characteristic pathology. Lancet 336, 7–9 (1990).

    Article  CAS  PubMed  Google Scholar 

  30. Serban, D., Taraboulos, A., DeArmond, S.J. & Prusiner, S.B. Rapid detection of Creutzfeldt-Jakob disease and scrapie prion proteins. Neurology 40, 110–117 (1990).

    Article  CAS  PubMed  Google Scholar 

  31. Laemmli, U.K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227, 680–685 (1970).

    Article  CAS  PubMed  Google Scholar 

  32. Jefferys, J.G.R., Whittington, M.A. & Empson, R.M. Thin film isolator for the preparation of, and making electrophysiological recording from, In vitro brain slices from scraple-lnfected mice and other biological hazards. J Physiol Lond 476, 9P (1994).

    Google Scholar 

  33. Davies, C.H., Davies, S.N. & Collingridge, G.L. Paired-pulse depression of monosynaptic GABA-mediated inhibitory postsynaptic responses In rat hippocampus. J. Physiol. Lond. 424, 513–531 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Whittington, M., Sidle, K., Gowland, I. et al. Rescue of neurophysiological phenotype seen in PrP null mice by transgene encoding human prion protein. Nat Genet 9, 197–201 (1995). https://doi.org/10.1038/ng0295-197

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0295-197

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