title: 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.
abstract: Creutzfeldt-Jakob disease (CJD) is a transmissible neurodegenerative disease of humans caused by an unidentified infectious agent, the prion. To determine whether there was an involvement of the host-encoded prion protein (PrPc) in CJD development and prion propagation, mice heterozygous (PrP+/-) or homozygous (PrP-/-) for a disrupted PrP gene were established and inoculated with the mouse-adapted CJD agent. In keeping with findings of previous studies using other lines of PrP-less mice inoculated with scrapie agents, no PrP-/- mice showed any sign of the disease for 460 days after inoculation, while all of the PrP+/- and control PrP+/+ mice developed CJD-like symptoms and died. The incubation 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 level at least 4 orders of magnitude lower than that in PrP+/+ mice. These findings indicate that PrPc is necessary for both the development of the disease and propagation of the prion in the inoculated mice. The proteinase-resistant PrP (PrPres) was undetectable in the brain tissues of the inoculated PrP-/- mice, while it accumulated in the affected brains of PrP+/+ and PrP+/- mice. Interestingly, the maximum level of PrPres in the brains of PrP+/- mice was about half of the level in the similarly affected brains of PrP+/+ mice, indicating that PrPres accumulation is restricted by the level of PrPc.
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology / Q000821:virology; D003001:Cloning, Molecular; D007562:Creutzfeldt-Jakob Syndrome / Q000473:pathology / Q000821:virology*; D006224:Cricetinae; D015342:DNA Probes; D004279:DNA, Viral / Q000032:analysis / Q000096:biosynthesis; D019286:Endopeptidase K; D015870:Gene Expression; D006801:Humans; D017403:In Situ Hybridization; D051379:Mice; D008817:Mice, Mutant Strains; D011328:Prions / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015183:Restriction Mapping; D012697:Serine Endopeptidases / Q000378:metabolism*; D013234:Stem Cells / Q000502:physiology; D013997:Time Factors
chemical_list: D015342:DNA Probes; D004279:DNA, Viral; D011328:Prions; D012697:Serine Endopeptidases; D019286:Endopeptidase K