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.