Codon 141 polymorphisms of the ovine prion protein gene affect the phenotype of classical scrapie transmitted from goats to sheep.

Abstract

BACKGROUND: A study to investigate transmission of classical scrapie via goat milk was carried out in sheep: firstly, lambs were challenged orally with goat scrapie brain homogenate to confirm transmission of scrapie from goats to sheep. In the second study phase, milk from scrapie-infected goats was fed to lambs. Lambs were selected according to their prion protein gene (PRNP) genotype, which was either VRQ/VRQ or ARQ/ARQ, with or without additional polymorphisms at codon 141 (FF, LFor LL) of the ovine PRNP. This report describes the clinical, pathological and molecular phenotype of goat scrapie in those sheep that progressed to clinical end-stage. RESULTS: Ten sheep (six VRQ/VRQ and four ARQ/ARQ, of which three FFand one LL) challenged with one of two scrapie brain homogenates, and six pairs of sheep (ARQ, of which five LLand seven LF) fed milk from six different goats, developed clinical disease, which was characterised by a pruritic (all VRQ/VRQ and LLsheep) or a non-pruritic form (all LFand FFsheep). Immunohistochemical (IHC) examination revealed that the pattern of intra- and extracellular accumulation of disease-associated prion protein in the brain was also dependent on PRNP polymorphisms at codon 141, which was similar in VRQ and LLsheep but different from LFand FFsheep. The influence of codon 141 was also seen in discriminatory Western blot (WB), with LFand FFsheep showing a bovine spongiform encephalopathy-like profile (diminished reactivity with P4 antibody) on brain tissue. However, discriminatory WB in lymphoid tissues, and IHC pattern and profile both in lymphoid and brain tissue was consistent with classical scrapie in all sheep. CONCLUSIONS: This study provided further evidence that the clinical presentation and the pathological and molecular phenotypes of scrapie in sheep are influenced by PRNP polymorphisms, particularly at codon 141. Differences in the truncation of disease-associated prion protein between LLsheep and those carrying the Fallele may be responsible for these observations.