Prion protein (PrP) with amino-proximal deletions restoring susceptibility of PrP knockout mice to scrapie

The 'protein only' hypothesis postulates that the prion, the agent causing transmissible spongiform encephalopathies, is PrPSc, an isoform of the host protein PrPC. Protease treatment of prion preparations cleaves off approximately 60 N-terminal residues of PrPSc but does not abrogate infectivity. Disruption of the PrP gene in the mouse abolishes susceptibility to scrapie and prion replication. We have introduced into PrP knockout mice transgenes encoding wild-type PrP or PrP lacking 26 or 49 amino-proximal amino acids which are protease susceptible in PrPSC. Inoculation with prions led to fatal disease, prion propagation and accumulation of PrPSc in mice expressing both wild-type and truncated PrPs. Within the framework of the 'protein only' hypothesis, this means that the amino-proximal segment of PrPC is not required either for its susceptibility to conversion into the pathogenic, infectious form of PrP or for the generation of PrPSc.