Goats naturally devoid of PrP ^C are 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 ^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.