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

Campbell, Lauren and Gill, Andrew and McGovern, Gillian and Jalland, Clara M.O and Hopkins, John and Tranulis, Michael A. and Hunter, Nora and Goldmann, Wilfred (2013) 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. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1832 (6). pp. 826-836. ISSN 0925-4439

Full content URL: http://doi.org/10.1016/j.bbadis.2013.02.020

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Item Type:Article
Item Status:Live Archive

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.

Additional Information:The final published version can be accessed online at https://www.sciencedirect.com/science/article/pii/S0925443913000653?via%3Dihub#ac0005
Keywords:prion, transmissible spongiform encephalopathies, fibrillisation, protein cleavage, JCCluster
Subjects:C Biological Sciences > C760 Biomolecular Science
C Biological Sciences > C770 Biophysical Science
Divisions:College of Science
ID Code:29469
Deposited On:01 Aug 2018 10:51

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