PRNP and prion disease: The process of template-directed self-replication of PrPSc constitutes the core of the “protein only” hypothesis (Prusiner et al., 1998), stating that the prion agent consists solely of misfolded PrPC conformers, and in accordance with this, PrPC knock-out (KO) mice do not replicate prions, nor do they develop prion disease (Bueler et al., 1992).