Prion Protein and Genetic Susceptibility to Diseases Caused by Its Misfolding

Early genetic studies on scrapie, an infectious neurodegenerative disease of sheep that was adapted to mice, provided evidence in support of the hypothesis that the agent was a slow virus with a nucleic acid genome independent of the host. Particularly compelling support for an independent genome came from the existence of strains of scrapie agent, some of which were true breeding, while others appeared to mutate under selective pressure. Kuru, a neurodegenerative disease in the remote highlands of Papua New Guinea, had pathological changes similar to those in scrapie and also proved to be transmissible. Genetic studies with the tools of molecular biology and transgenic mice forced a reevaluation of earlier work and supported the prion hypothesis of a novel pathogen devoid of nucleic acid. In this chapter, I discuss the contributions of classical and molecular genetics to understanding PrP prion diseases and to determining that heritable information is enciphered in protein conformation.