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9 - Structure–function analysis of prion protein
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- By Charles Weissmann, MRC Prion Unit/Neurogenetics, Imperial College School of Medicine at St Mary's, London W2 1PG, UK, Doron Shmerling, MRC Prion Unit/Neurogenetics, Imperial College School of Medicine at St Mary's, London W2 1PG, UK, Current address: Core Technologies Dept, Novartis Pharma AG, 4002 Basel, Switzerland., Daniela Rossi, MRC Prion Unit/Neurogenetics, Imperial College School of Medicine at St Mary's, London W2 1PG, UK, Antonio Cozzio, MRC Prion Unit/Neurogenetics, Imperial College School of Medicine at St Mary's, London W2 1PG, UK, Current address: Dept of Pathology, Stanford University School of Medicine, Stanford, CA 94304, USA., Ivan Hegyi, Institut für Neuropathologie, Universitätsspital Zürich, 8091 Zürich, Switzerland, Marek Fischer, MRC Prion Unit/Neurogenetics, Imperial College School of Medicine at St Mary's, London W2 1PG, UK, Current address: Dept für Innere Medizin, Abt. für Infektionskrankheiten, Universitätsspital Zürich, Zürich 8091, Switzerland., Rainer Leimeroth, MRC Prion Unit/Neurogenetics, Imperial College School of Medicine at St Mary's, London W2 1PG, UK, Current address: Dept of Cell Biology, ETH, Hönggerberg, 8093 Zürich, Switzerland., Eckhard Flechsig, MRC Prion Unit/Neurogenetics, Imperial College School of Medicine at St Mary's, London W2 1PG, UK
- Edited by G. L. Smith, Imperial College of Science, Technology and Medicine, London, W. L. Irving, University of Nottingham, J. W. McCauley, Institute for Animal Health, Compton, Berkshire, D. J. Rowlands, University of Leeds
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- Book:
- New Challenges to Health
- Published online:
- 06 July 2010
- Print publication:
- 19 April 2001, pp 179-194
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Summary
INTRODUCTION
PrP, the prion protein, plays a central role in the pathogenesis of transmissible spongiform encephalopathies such as scrapie or bovine spongiform encephalopathy (BSE) (Prusiner, 1996, 1998; Weissmann, 1999; Weissmann et al., 1996). The normal form of PrP, designated PrPC, is encoded by a single-copy gene (Basler et al., 1986) and is expressed in the brain of healthy and prion-infected organisms to about the same extent (Chesebro et al., 1985; Oesch et al., 1985). There is overwhelming evidence that a modified form of PrPC, which we designate PrP* (Weissmann, 1991), is the principal if not the only component of the infectious agent, or prion, and that it is devoid of nucleic acid. The ‘protein-only’ hypothesis (Griffith, 1967) states that the abnormal form of PrP propagates by interacting with PrPC and converting it into a likeness of itself (Prusiner, 1989, 1996; Weissmann et al., 1996). It has been proposed that a partially protease-resistant, aggregated form of PrP, named PrPSc or PrP-res, is congruent with PrP* (Prusiner, 1989).
Mice devoid of PrP develop and behave normally (Büeler et al., 1992) but are resistant to prion disease (Büeler et al., 1993; Manson et al., 1994; Sailer et al., 1994; Sakaguchi et al., 1995). Moreover, introduction of PrP transgenes into such Prnp0/0 mice restores susceptibility to scrapie (Fischer et al., 1996), thus paving the way for structure–function analysis of PrP.
In this chapter, we review our deletion analysis of PrP with regard to its ability to mediate scrapie pathogenesis and prion replication as well as some aspects of its conjectured natural function.
Neuroinvasion of prions: insights from mouse models
- Sebastian Brandner*, Michael A. Klein, Rico Frigg, Valdimir Pekarik, Petra Parizek, Alex Raeber, Markus Glatzel, Petra Schwarz, Thomas Rulicke, Charles Weissmann, Adriano Aguzzi
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- Journal:
- Experimental Physiology / Volume 85 / Issue 6 / November 2000
- Published online by Cambridge University Press:
- 10 January 2001, pp. 705-712
- Print publication:
- November 2000
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The prion was defined by Stanley B. Prusiner as the infectious agent that causes transmissible spongiform encephalopathies. A pathological protein accumulating in the brain of scrapie-infected hamsters was isolated in 1982 and termed prion protein (PrPSc). Its cognate gene Prnp was identified more than a decade ago by Charles Weissmann, and shown to encode the host protein PrPC. Since the latter discovery, transgenic mice have contributed many important insights into the field of prion biology, including the understanding of the molecular basis of the species barrier for prions. By disrupting the Prnp gene, it was shown that an organism that lacks PrPC is resistant to infection by prions. Introduction of mutant PrP genes into PrP-deficient mice was used to investigate the structure-activity relationship of the PrP gene with regard to scrapie susceptibility. Ectopic expression of PrP in PrP knockout mice proved a useful tool for the identification of host cells competent for prion replication. Finally, the availability of PrP knockout mice and transgenic mice overexpressing PrP allows selective reconstitution experiments aimed at expressing PrP in neurografts or in specific populations of haemato- and lymphopoietic cells. The latter studies have allowed us to clarify some of the mechanisms of prion spread and disease pathogenesis.