The PrPC Cl fragment derived from the ovine A(136)R(154)R(171) PRNP allele is highly abundant in sheep brain and inhibits fibrillisation of full-length PrPC protein in vitro

Lauren Campbell, Andrew C. Gill, Gillian McGovern, Clara M. O. Jalland, John Hopkins, Michael A. Tranulis, Nora Hunter, Wilfred Goldmann*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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 alpha-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 a-cleavage of ovine ARR PrPC contributes to a dominant negative effect of this polymorphism on disease susceptibility. Furthermore, the significant reduction in PrPC beta-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. Crown Copyright (C) 2013 Published by Elsevier B.V. All rights reserved.

Original languageEnglish
Pages (from-to)826-836
Number of pages11
JournalBBA - Molecular Basis of Disease
Volume1832
Issue number6
Early online date6 Mar 2013
DOIs
Publication statusPublished - Jun 2013

Keywords

  • SECONDARY STRUCTURE
  • Fibrillization
  • AMYLOID FIBRILS
  • Prion
  • CLEAVAGE
  • HUMAN PRION PROTEIN
  • TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES
  • Transmissible spongiform encephalopathy
  • OXIDATIVE STRESS
  • NATURAL SCRAPIE
  • DISEASE
  • CELL-FREE CONVERSION
  • Protein-cleavage
  • POLYMORPHISMS

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