Goats naturally devoid of PrPC 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.

Prion protein lowering is a disease-modifying therapy across prion disease stages, strains and endpoints

“…Due to its central role in disease pathophysiology, reduction of native PrP is an attractive therapeutic hypothesis in prion disease ( 2 ). Homozygous deletion of PrP prevents prion infection ( 3 , 4 ), while heterozygous PrP knockout delays development of disease following prion infection ( 4–7 ) and transgenic PrP overexpression accelerates it ( 8 ), providing genetic evidence of a continuous dose-response relationship between PrP dosage and disease susceptibility. Conditional knockout systems have confirmed that post-natal depletion confers significant survival benefit, even in the presence of low levels of residual PrP expression ( 9 , 10 ).…”

“…For PrP-lowering therapy to advance effectively, a number of fundamental questions must be addressed. While heterozygous knockout animals show a clear benefit to 50% PrP reduction ( 4–7 ), the minimal threshold of PrP knockdown needed to confer benefit has not been established. The existence of different prions strains, or subtypes, has complicated previous drug development efforts: antiprion compounds with non-PrP-lowering mechanisms of action have failed to generalize across strains ( 29–33 ), and prions have been shown capable of adapting to drug treatment, giving rise to new drug-resistant strains ( 30 , 34 , 35 ).…”

Prion protein lowering is a disease-modifying therapy across prion disease stages, strains, and endpoints

“…Due to its central role in disease pathophysiology, reduction of native PrP is an attractive therapeutic hypothesis in prion disease 2 . Homozygous deletion of PrP prevents prion infection 3,4 , while heterozygous PrP knockout delays development of disease following prion infection [4][5][6][7] and transgenic PrP overexpression accelerates it 8 , providing genetic evidence of a continuous doseresponse relationship between PrP dosage and disease susceptibility. Conditional knockout systems have confirmed that post-natal depletion confers significant survival benefit, even in the presence of low levels of residual PrP expression 9,10 .…”

“…For PrP-lowering therapy to advance effectively, a number of fundamental questions must be addressed. While heterozygous knockout animals show a clear benefit to 50% PrP reduction [4][5][6][7] , the minimal threshold of PrP knockdown needed to confer benefit has not been established. The existence of different prions strains, or subtypes, has complicated previous drug development efforts: antiprion compounds with non-PrP-lowering mechanisms of action have failed to generalize across strains [29][30][31][32][33] , and prions have been shown capable of adapting to drug treatment, giving rise to new drug-resistant strains 30,34,35 .…”

Annual Report of the Scientific Network on BSE‐TSE 2020

“…The representative of Norway presented the results of on recently published scientific articles of interest, of which he is co-author: "Goats naturally devoid of PrP C are resistant to scrapie", Salvesen et al (2020). The nonsense mutation at codon 32 in the prion protein (PRNP) open reading frame (ORF) -discovered during routine PRNP genetic analysis in dairy goats in Norway -has raised the question of the resistance to scrapie.…”