Goats naturally devoid of PrP^C are resistant to scrapie

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^C) is converted into a pathological and infectious form (PrP^Sc) in these diseases. Transgenic knockout models have shown that PrP^C is a prerequisite for the development of prion disease. In Norwegian dairy goats, a mutation (Ter) in the prion protein gene (PRNP) effectively blocks PrP^C synthesis. We inoculated 12 goats (4 PRNP^+/+, 4 PRNP^+/Ter, and 4 PRNP^Ter/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. PrP^Sc 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 PrP^Sc was limited in peripheral organs, but all PRNP^+/+ goats and 1 of 4 PRNP^+/Ter goats were positive in head lymph nodes. The four PRNP^Ter/Ter goats remained healthy, without clinical signs of prion disease, and were euthanized 1260 dpi. As expected, no accumulation of PrP^Sc 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 PrP^C 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 PrP^C levels.