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 diseases are fatal neurodegenerative disorders with known natural occurrence in humans and a few other mammalian species. The diseases are experimentally transmissible, and the agent is derived from the host-encoded cellular prion protein (PrP^C), which is misfolded into a pathogenic conformer, designated PrP^Sc (scrapie). Aggregates of PrP^Sc molecules, constitute proteinaceous infectious particles, known as prions. Classical scrapie in sheep and goats and chronic wasting disease (CWD) in cervids are known to be infectious under natural conditions. In CWD, infected animals can shed prions via bodily excretions, allowing direct host-to-host transmission or indirectly via prion-contaminated environments. The robustness of prions means that transmission via the latter route can be highly successful and has meant that limiting the spread of CWD has proven difficult. In 2016, CWD was diagnosed for the first time in Europe, in reindeer (Rangifer tarandus) and European moose (Alces alces). Both were diagnosed in Norway, and, subsequently, more cases were detected in a semi-isolated wild reindeer population in the Nordfjella area, in which the first case was identified. This population was culled, and all reindeer (approximately 2400) were tested for CWD; 18 positive animals, in addition to the first diagnosed case, were found. After two years and around 25,900 negative tests from reindeer (about 6500 from wild and 19,400 from semi-domesticated) in Norway, a new case was diagnosed in a wild reindeer buck on Hardangervidda, south of the Nordfjella area, in 2020. Further cases of CWD were also identified in moose, with a total of eight in Norway, four in Sweden, and two cases in Finland. The mean age of these cases is 14.7 years, and the pathological features are different from North American CWD and from the Norwegian reindeer cases, resembling atypical prion diseases such as Nor98/atypical scrapie and H- and L-forms of BSE. In this review, these moose cases are referred to as atypical CWD. In addition, two cases were diagnosed in red deer (Cervus elaphus) in Norway. The emergence of CWD in Europe is a threat to European cervid populations, and, potentially, a food-safety challenge, calling for a swift, evidence-based response. Here, we review data on surveillance, epidemiology, and disease characteristics, including prion strain features of the newly identified European CWD agents.

The cellular prion protein PrP^C is highly expressed in neurons, but also present in non-neuronal tissues, including the testicles and spermatozoa. Most immune cells and their bone marrow precursors also express PrP^C. Clearly, this protein operates in highly diverse cellular contexts. Investigations into putative stress-protective roles for PrP^C have resulted in an array of functions, such as inhibition of apoptosis, stimulation of anti-oxidant enzymes, scavenging roles, and a role in nuclear DNA repair. We have studied stress resilience of spermatozoa and peripheral blood mononuclear cells (PBMCs) derived from non-transgenic goats that lack PrP^C (PRNP^Ter/Ter) compared with cells from normal (PRNP^+/+) goats. Spermatozoa were analyzed for freeze tolerance, DNA integrity, viability, motility, ATP levels, and acrosome intactness at rest and after acute stress, induced by Cu²⁺ ions, as well as levels of reactive oxygen species (ROS) after exposure to FeSO₄ and H₂O₂. Surprisingly, PrP^C-negative spermatozoa reacted similarly to normal spermatozoa in all read-outs. Moreover, in vitro exposure of PBMCs to Doxorubicin, H₂O₂ and methyl methanesulfonate (MMS), revealed no effect of PrP^C on cellular survival or global accumulation of DNA damage. Similar results were obtained with human neuroblastoma (SH-SY5Y) cell lines stably expressing varying levels of PrP^C. RNA sequencing of PBMCs (n = 8 of PRNP^+/+ and PRNP^Ter/Ter) showed that basal level expression of genes encoding DNA repair enzymes, ROS scavenging, and antioxidant enzymes were unaffected by the absence of PrP^C. Data presented here questions the in vitro cytoprotective roles previously attributed to PrP^C, although not excluding such functions in other cell types or tissues during inflammatory stress.

Despite intensive studies since the 1990s, the physiological role of the cellular prion protein (PrPC) remains elusive. Here, we present a novel concept suggesting that PrPC contributes to immunological quiescence in addition to cell protection. PrPC is highly expressed in diverse organs that by multiple means are particularly protected from inflammation, such as the brain, eye, placenta, pregnant uterus and testes, while at the same time it is expressed in most cells of the lymphoreticular system. In this paradigm, PrPC serves two principal roles: to modulate the inflammatory potential of immune cells and to protect vulnerable parenchymal cells against noxious insults generated through inflammation. Here we review studies of PrPC physiology in view of this concept.

The cellular prion protein (PrPC) is an evolutionary conserved protein abundantly expressed not only in the central nervous system but also peripherally including the immune system. A line of Norwegian dairy goats naturally devoid of PrPC (PRNP Ter/Ter) provides a novel model for studying PrPC physiology. In order to explore putative roles for PrPC in acute inflammatory responses, we performed a lipopolysaccharide (LPS, Escherichia coli O26:B6) challenge of 16 goats (8 PRNP +/+ and 8 PRNP Ter/Ter) and included 10 saline-treated controls (5 of each PRNP genotype). Clinical examinations were performed continuously, and blood samples were collected throughout the trial. Genome-wide transcription profiles of the choroid plexus, which is at the blood-brain interface, and the hippocampus were analyzed by RNA sequencing, and the same tissues were histologically evaluated. All LPS-treated goats displayed clinical signs of sickness behavior, which were of significantly (p < 0.01) longer duration in animals without PrPC. In the choroid plexus, a substantial alteration of the transcriptome and activation of Iba1-positive cells were observed. This response included genotype-dependent differential expression of several genes associated with the immune response, such as ISG15, CXCL12, CXCL14, and acute phase proteins, among others. Activation of cytokine-responsive genes was skewed towards a more profound type I interferon response, and a less obvious type II response, in PrPC-deficient goats. The magnitude of gene expression in response to LPS was smaller in the hippocampus than in the choroid plexus. Resting state expression profiles revealed a few differences between the PRNP genotypes. Our data suggest that PrPC acts as a modulator of certain pathways of innate immunity signaling, particularly downstream of interferons, and probably contributes to protection of vulnerable tissues against inflammatory damage.

Studies in mice with ablation of Prnp , the gene that encodes the cellular prion protein (PrP ^C ), have led to the hypothesis that PrP ^C is important for peripheral nerve myelin maintenance. Here, we have used a nontransgenic animal model to put this idea to the test; namely, goats that, due to a naturally occurring nonsense mutation, lack PrP ^C . Teased nerve fiber preparation revealed a demyelinating pathology in goats without PrP ^C . Affected nerves were invaded by macrophages and T cells and displayed vacuolated fibers, shrunken axons, and onion bulbs. Peripheral nerve lipid composition was similar in young goats with or without PrP ^C , but markedly different between corresponding groups of adult goats, reflecting the progressive nature of the neuropathy. This is the first report of a subclinical demyelinating polyneuropathy caused by loss of PrP ^C function in a nontransgenic mammal.