Neuroinvasion of prions: insights from mouse models

The prion was defined by Stanley B. Prusiner as the infections agent that c auses transmissible spongiform encephalopathies. A pathological protein acc umulating in the brain of scrapie-infected hamsters was isolated in 1982 an d termed prion protein (PrPSc). Its cognate gene Pmp was identified more th an a decade ago by Charles Weissmann, and shown to encode the host protein PrPC. Since the latter discovery, transgenic mice have contributed many imp ortant insights into the Field of prion biology, including the understandin g of the molecular basis of the species barrier for prions. By disrupting t he 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 mi ce was used to investigate the structure-activity relationship of the PrP g ene with regard to scrapie susceptibility. Ectopic expression of PrP in PrP knockout mice proved a useful tool for the identification of host cells co mpetent for prion replication. Finally, the availability of PrP knockout mi ce and transgenic mice overexpressing PrP allows selective reconstitution e xperiments aimed at expressing PrP in neurografts or in specific population s of haemato- and lymphopoietic cells. The latter studies have allowed us t o clarify some of the mechanisms of prion spread and disease pathogenesis.