Mechanisms of neuroinvasion by prions: molecular principles and present status of research

The prion was defined by Stanley Prusiner as the infectious agent that caus es transmissible spongiform encephalopathies and equated with the prion pro tein PrPSc. Its cognate gene, Prnp, was identified by Charles Weissmann in Zurich, and shown to encode the host protein PrPC. Since the latter discove ry, transgenic mice have contributed many important insights to the field o f prion biology, including an understanding of the molecular basis of the s pecies barrier for prions. By disrupting the Pmp 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 st ructure-activity relationship of the PrP gene with regard to scrapie suscep tibility. Ectopic expression of PrP in Prnp-knockout mice provided a useful strategy for the identification of host cells competent for prion replicat ion. Finally, the availability of Prnp-knockout mice and transgenic mice ov erexpressing PrP allows selective reconstitution experiments aimed at expre ssing PrP in neurografts or in specific populations of haemato- and lymphop oietic cells. The latter studies have allowed us to clarify some of the mec hanisms of prion spread and disease pathogenesis.