The PrPC C1 fragments derived from ovine PRNP alleles exhibit different abundance in brain and in vitro fibrillisation characteristics.

Expression of the cellular prion protein (PrPC) is crucial for the development of prion diseases. Therefore, resistance to prion diseases can result from reduced availability of the prion protein or from amino acid changes in the prion protein sequence. We propose here that increased production of a natural PrP α-cleavage fragment, C1, is also associated with resistance to disease. Our data show that steady state levels of the C1 fragment relative to total PrPC were 1.8 times higher in the cortex of ARR homozygous sheep (RR171), associated with resistance to disease, when compared to disease-susceptible ARQ homozygous sheep (QQ171). Unexpectedly, only the C1 fragment derived from the ARR allele inhibited in-vitro fibrillisation of other allelic PrPC variants. We hypothesis that the increased α-cleavage of ovine ARR PrPC contributes to a dominant negative effect of this polymorphism on disease susceptibility. Furthermore, the RR171 samples were five times less likely to show PrPC β-cleavage product C2 than QQ171 genotypes (p ≤ 0.01). This significant reduction in C2 in sheep of the resistant genotype may add to the complexity of genetic determinants of prion disease susceptibility. The next aim is to investigate the proteases involved in PrPC processing for their specificity and possible genetic variation. The cleavage of PrPC may be a suitable therapeutic target in prion disease.

Acknowledgement
This project was supported through a strategic programme grant to The Roslin Institute by the Biotechnology and Biological Sciences Research Council, UK.