To understand the functional role of cellular prion protein (PrP(C)) in the initiation and maintenance of prion disease within the host, it is important to obtain a more detailed understanding of PrP(C) transcription in tissues during the development of disease. Using an experimental model with oral infection, we examined the effect of scrapie and the accumulation of the scrapie related form of the prion protein (PrP(Sc)) on the expression level of PrP mRNA in the ileal Peyer's patch of sheep. In the early phase of infection, prior to PrP(Sc) accumulation, no effect on the PrP expression was detected. However, it was found that lambs with PrP genotypes associated with high susceptibility for scrapie generally had higher PrP mRNA levels than lambs with less susceptible genotypes. Further, in highly susceptible VRQ/VRQ sheep at a stage of disease with high accumulation of PrP(Sc), real-time RT-PCR and microdissection were used to investigate levels of PrP mRNA in four different tissue compartments. An increased level of PrP mRNA was found in lymphoid follicles of infected sheep compared with controls, indicating upregulation of PrP expression in the follicles to compensate for the loss of PrP(C) converted to PrP(Sc), or that PrP(Sc) accumulation directly or indirectly influences the PrP expression. Still, the PrP expression level in the follicles was low compared with the other compartments investigated, suggesting that although increased PrP expression could contribute to PrP(Sc) accumulation, other factors are also important in the processes leading to accumulation of PrP(Sc) in the follicles.