ACCUMULATION OF PROTEINASE K-RESISTANT PRION PROTEIN (PRP) IS RESTRICTED BY THE EXPRESSION LEVEL OF NORMAL PRP IN MICE INOCULATED WITH A MOUSE-ADAPTED STRAIN OF THE CREUTZFELDT-JAKOB-DISEASE AGENT

Creutzfeldt-Jakob disease (CJD) is a transmissible neurodegenerative d isease of humans caused by an unidentified infectious agent, the prion . To determine whether there was an involvement of the host-encoded pr ion protein (PrPc) in CJD development and prion propagation, mice hete rozygous (PrP+/-) or homozygous (PrP-/-) for a disrupted PrP gene were established and inoculated with the mouse-adapted CJD agent. In keepi ng with findings of previous studies using other lines of PrP-less mic e inoculated with scrapie agents, no PrP-/- mice showed any sign of th e disease for 460 days after inoculation, while all of the PrP+/- and control PrP+/+ mice developed CJD-like symptoms and died. The incubati on period for PrP+/- mice, 259 +/- 27 days, was much longer than that for PrP+/+ mice, 138 +/- 12 days. Propagation of the prion was barely detectable in the brains of PrP-/- mice and was estimated to be at a l evel at least 4 orders of magnitude lower than that in PrP+/+ mice. Th ese findings indicate that PrPc is necessary for both the development of the disease and propagation of the prion in the inoculated mice. Th e proteinase-resistant PrP (PrPres) was undetectable in the brain tiss ues of the inoculated PrP-/- mice, while it accumulated in the affecte d brains of PrP+/+ and PrP+/- mice. Interestingly, the maximum level o f PrPres in the brains of PrP+/- mice was about half of the level in t he similarly affected brains of PrP+/+ mite, indicating that PrPres ac cumulation is restricted by the level of PrPc.