Goats naturally devoid of PrPare resistant to scrapie.

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 (PrP) is converted into a pathological and infectious form (PrP) in these diseases. Transgenic knockout models have shown that PrPis a prerequisite for the development of prion disease. In Norwegian dairy goats, a mutation (Ter) in the prion protein gene (PRNP) effectively blocks PrPsynthesis. We inoculated 12 goats (4 PRNP, 4 PRNP, and 4 PRNP) intracerebrally with goat scrapie prions. The mean incubation time until clinical signs of prion disease was 601 days post-inoculation (dpi) in PRNPgoats and 773 dpi in PRNPgoats. PrPand 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 PrPwas limited in peripheral organs, but all PRNPgoats and 1 of 4 PRNPgoats were positive in head lymph nodes. The four PRNPgoats remained healthy, without clinical signs of prion disease, and were euthanized 1260 dpi. As expected, no accumulation of PrPwas 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 PrPdue 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 PrPlevels.