Prions: Pathogenesis and Reverse Genetics

A bstract : Spongiform encephalopathies are a group of infectious neurodegenerative diseases. The infectious agent that causes transmissible spongiform encephalopathies was termed prion by Stanley Prusiner. The prion hypothesis states that the partially protease‐resistant and detergent‐insoluble prion protein (PrP sc ) is identical with the infectious agent, and lacks any detectable nucleic acids. Since the latter discovery, transgenic mice have contributed many important insights into the field of prion biology. The prion protein (PrP c ) is encoded by the Prnp gene, and disruption of Prnp leads to resistance to infection by prions. Introduction of mutant PrP c genes into PrP c ‐deficient mice was used to investigate structure‐activity relationships of the PrP c gene with regard to scrapie susceptibility. Ectopic expression of PrP c in PrP c knockout mice proved a useful tool for the identification of host cells competent for prion replication. Finally, the availability of PrP c knockout and transgenic mice overexpressing PrP c allowed selective reconstitution experiments aimed at expressing PrP c in neurografts or in specific populations of hemato‐ and lymphopoietic cells. The latter studies helped in elucidating some of the mechanisms of prion spread and disease pathogenesis.