Goats naturally devoid of PrPC are resistant to scrapie

Øyvind Salvesen,Michael A Tranulis,Arild Espenes,Tram T Vuong,Cecilie Ersdal,Ingrid Olsaker,Giulia Malachin,Linh Tran,Malin R Reiten,Olivier Andréoletti,Sylvie L Benestad

doi:10.1186/s13567-019-0731-2

Abstract

Prion diseases are progressive and fatal, neurodegenerative disorders described in humans and animals. According to the “protein-only” hypothesis, the normal host-encoded prion protein (PrPC) is converted into a pathological and infectious form (PrPSc) in these diseases. Transgenic knockout models have shown that PrPC is a prerequisite for the development of prion disease. In Norwegian dairy goats, a mutation (Ter) in the prion protein gene (PRNP) effectively blocks PrPC synthesis. We inoculated 12 goats (4 PRNP+/+, 4 PRNP+/Ter, and 4 PRNPTer/Ter) intracerebrally with goat scrapie prions. The mean incubation time until clinical signs of prion disease was 601 days post-inoculation (dpi) in PRNP+/+ goats and 773 dpi in PRNP+/Ter goats. PrPSc and vacuolation were similarly distributed in the central nervous system (CNS) of both groups and observed in all brain regions and segments of the spinal cord. Generally, accumulation of PrPSc was limited in peripheral organs, but all PRNP+/+ goats and 1 of 4 PRNP+/Ter goats were positive in head lymph nodes. The four PRNPTer/Ter goats remained healthy, without clinical signs of prion disease, and were euthanized 1260 dpi. As expected, no accumulation of PrPSc was observed in the CNS or peripheral tissues of this group, as assessed by immunohistochemistry, enzyme immunoassay, and real-time quaking-induced conversion. Our study shows for the first time that animals devoid of PrPC due to a natural mutation do not propagate prions and are resistant to scrapie. Clinical onset of disease is delayed in heterozygous goats expressing about 50% of PrPC levels.

Highlights

Prion diseases are a group of fatal, neurodegenerative disorders that occur in humans and a range of animals
Clinical signs of prion disease are delayed in prion protein gene (PRNP)+/Ter goats Figure 1 summarizes the clinical progression of nine selected clinical signs in the 12 goats (4 PRNP+/+, 4 PRNP+/Ter and 4 PRNPTer/Ter) included in the study
The four PRNPTer/Ter goats remained healthy without any clinical signs of prion disease until they were euthanized 1260 dpi

Summary

Introduction

Prion diseases are a group of fatal, neurodegenerative disorders that occur in humans and a range of animals. Among these are Creutzfeldt-Jakob disease in humans, bovine spongiform encephalopathy in cattle, chronic wasting disease in cervids, and scrapie in sheep and goats. Of particular interest are the S146 and K222 polymorphisms that delay clinical disease beyond the productive lifetime of goats upon experimental inoculation with scrapie [12,13,14,15]. These polymorphisms are found in a variety of goat breeds the allele frequencies are relatively low [16,17,18].

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Results

Conclusion