Markedly increased susceptibility to natural sheep scrapie of transgenic mice expressing ovine PrP

The susceptibility of sheep to scrapie is known to involve, as a major dete rminant, the nature of the prion protein (PrP) allele, with the VRQ allele conferring the highest susceptibility to the disease, Transgenic mice expre ssing in their brains three different ovine PrPVRQ-encoding transgenes unde r an endogenous PrP-deficient genetic background were established, Nine tra nsgenic (tgOv) lines were selected and challenged with two scrapie field is olates derived from VRQ-homozygous affected sheep, All inoculated mice deve loped neurological signs associated with a transmissible spongiform encepha lopathy (TSE) disease and accumulated a protease-resistant form of PrP (PrP res) in their brains. The incubation duration appeared to be inversely rela ted to the PrP steady-state level in the brain, irrespective of the transge ne construct. The survival time for animals from the line expressing the hi ghest level of PrP was reduced by at least 1 year compared to those of two groups of conventional mice. With one isolate, the duration of incubation w as as short as 2 months, which is comparable to that observed for the roden t TSE models with the briefest survival times. No survival time reduction w as observed upon subpassaging of either isolate, suggesting no need for ada ptation of the agent to its new host, Overexpression of the transgene was f ound not to be required for transmission to be accelerated compared to that observed with wild-type mice. Conversely, transgenic mice overexpressing m urine PrP were found to be less susceptible than tgOv lines expressing ovin e PrP at physiological levels. These data argue that ovine PrPVRQ provided a better substrate for sheep prion replication than did mouse PrP. Altogeth er, these tgOv mice could be an improved model for experimental studies on natural sheep scrapie.