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

Abstract

BackgroundA 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 (FF141, LF141 or LL141) 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.ResultsTen sheep (six VRQ/VRQ and four ARQ/ARQ, of which three FF141 and one LL141) challenged with one of two scrapie brain homogenates, and six pairs of sheep (ARQ, of which five LL141 and seven LF141) fed milk from six different goats, developed clinical disease, which was characterised by a pruritic (all VRQ/VRQ and LL141 sheep) or a non-pruritic form (all LF141 and FF141 sheep). 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 LL141 sheep but different from LF141 and FF141 sheep. The influence of codon 141 was also seen in discriminatory Western blot (WB), with LF141 and FF141 sheep 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.ConclusionsThis 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 LL141 sheep and those carrying the F141 allele may be responsible for these observations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12917-017-1036-1) contains supplementary material, which is available to authorized users.

Low-volume goat milk transmission of classical scrapie to lambs and goat kids

“…Accumulation of PrP Sc in RAMALT was not observed in the biopsy samples from the remaining sheep or any of the goats. Observed transmission of classical scrapie from goat milk to sheep at 18 mpi was similar to previous observations even though sheep in the current study consumed approximately one-tenth the volume of goat milk that resulted in scrapie infection in a study by Konold and colleagues [ 16 , 17 , 47 ]. Animals in the current study were housed as groups (sheep separate from goats) and lateral transmission from ovine milk inoculated sheep to co-housed flock mates has been described previously [ 10 ].…”

Characterization of goat prions demonstrates geographical variation of scrapie strains in Europe and reveals the composite nature of prion strains

“…CH1641 is an experimental scrapie strain that was originally isolated from a British scrapie case and propagated by serial transmission in sheep. Our results may suggest that serial intracerebral transmission in sheep led to positive selection of 19 K over 21 K in CH1641, given the neurotropism of 19 K and evidences that experimental transmission per se could mediate the emergence of CH1641-like properties in recipient sheep 46,57 . Interestingly, it has been shown that the PrP Sc type in natural CH1641-like isolates does not fully match experimental CH1641, but shows intermediate properties between classical scrapie and experimental CH1641 suggesting the co-existence of 19 K and 21 K in a mixture 27 .…”

Review: Update on Classical and Atypical Scrapie in Sheep and Goats

“…60 Furthermore, codon 141 polymorphisms affect the phenotype of classical scrapie, including clinical presentation and molecular phenotypes. 95 At least 50 PRNP polymorphisms have been described in goat breeds, 1,36 but how they affect incubation times and susceptibility to classical scrapie is less defined than in sheep. Amino acid substitutions that may affect susceptibility to classical scrapie include G127 S, 57 I142 M, 56 N146S/D, 124 H154 R, 10,20,125,158 Q211 R, 10 and Q222 K. 2,10,158 The M142 polymorphism appears to prolong incubation period in experimental studies 56 but not confer resistance to classical scrapie.…”