Abstract
In sheep polymorphisms of the prion gene (PRNP) at the codons 136, 154 and 171 strongly influence the susceptibility to scrapie and bovine spongiform encephalopathy (BSE) infections. In goats a number of other gene polymorphisms were found which are suspected to trigger similar effects. However, no strong correlation between polymorphisms and TSE susceptibility in goats has yet been obtained from epidemiological studies and only a low number of experimental challenge data are available at present. We have therefore studied the potential impact of these polymorphisms in vitro by cell-free conversion assays using mouse scrapie strain Me7. Mouse scrapie brain derived PrPSc served as seeds and eleven recombinant single mutation variants of sheep and goat PrPC as conversion targets. With this approach it was possible to assign reduced conversion efficiencies to specific polymorphisms, which are associated to low frequency in scrapie-affected goats or found only in healthy animals. Moreover, we could demonstrate a dominant-negative inhibition of prion polymorphisms associated with high susceptibility by alleles linked to low susceptibility in vitro.
Highlights
Prion diseases include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle and CreutzfeldtJacob-Disease (CJD) in humans and are characterized by the conversion of cellular prion protein (PrPC) into an abnormal pathological isoform called PrPSc
Cell-free conversion assays were widely used for the determination of PrP conversion efficiencies and evaluation of species barriers in vitro
We report the conversion of ovine and caprine polymorphisms in vitro and their association with susceptibility to scrapie in vivo
Summary
Prion diseases include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle and CreutzfeldtJacob-Disease (CJD) in humans and are characterized by the conversion of cellular prion protein (PrPC) into an abnormal pathological isoform called PrPSc. Sheep carrying the PRNP polymorphisms valine (V) or alanine (A) at codon 136 (136V and 136A) are highly susceptible to classical scrapie, while the exchange of arginine (R) to histidine at codon 154 (154H) is linked to low scrapie susceptibility [1,2] This allele is Genetic analysis of the goat PRNP revealed 42 polymorphisms in the open reading frame including silent mutations [9]. Some of these polymorphisms are associated with changes in the susceptibility to scrapie: At codon 142 an exchange from isoleucine (I) to methionine (M) (142M) prolongs the incubation time after a challenge with scrapie and BSE prions [10]. The caprine wildtype allele contained isoleucin (I) at position 142, histidine (H) at position 143, asparagine (N) at position 146, arginine (R)
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