The PrPC C1 fragment derived from the ovine A136R154R171 PRNP allele is highly abundant in sheep brain and inhibits fibrillisation of full-length PrPC protein in vitro |
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| Authors: | Lauren Campbell Andrew C Gill Gillian McGovern Clara MO Jalland John Hopkins Michael A Tranulis Nora Hunter Wilfred Goldmann |
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| Institution: | 1. The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, Scotland, UK;2. Animal Health and Veterinary Laboratories Agency (AHVLA), AHVLA-Lasswade, Pentlands Science Park, Penicuick, Midlothian, UK;3. Institute of Basic Sciences and Aquatic Medicine, Department of Biochemistry and Physiology, Norwegian School of Veterinary Science, Oslo, Norway;4. The Roslin Institute, Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian, Scotland, UK |
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| Abstract: | Expression of the cellular prion protein (PrPC) is crucial for the development of prion diseases. 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. We show, in brain tissue, that ARR homozygous sheep, associated with resistance to disease, produced PrPC comprised of 25% more C1 fragment than PrPC from the disease-susceptible ARQ homozygous and highly susceptible VRQ homozygous animals. Only the C1 fragment derived from the ARR allele inhibits in-vitro fibrillisation of other allelic PrPC variants. We propose that the increased α-cleavage of ovine ARR PrPC contributes to a dominant negative effect of this polymorphism on disease susceptibility. Furthermore, the significant reduction in PrPC β-cleavage product C2 in sheep of the ARR/ARR genotype compared to ARQ/ARQ and VRQ/VRQ genotypes, may add to the complexity of genetic determinants of prion disease susceptibility. |
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