Scrapie Research Articles

Evaluation of the application of Slovenia to be recognised as having a negligible risk of classical scrapie.

Slovenia submitted a request to the European Commission to be recognised as a Member State with negligible risk of classical scrapie. EFSA has been asked to assess if Slovenia has demonstrated that, between 2016 and 2022, a sufficient number of ovine and caprine animals over 18 months old, representative of those slaughtered, culled or found dead have been tested, and will continue to be tested annually, to provide a 95% confidence of detecting classical scrapie if it is present at a prevalence rate exceeding 0.1%. A risk-based approach using stochastic scenario tree modelling accounting for surveillance stream and species was applied. Globally, there is still a lack of data on the performance of the approved diagnostic screening tests under field conditions, specifically for sheep. Therefore, alternative scenarios were explored extending the range from the sensitivity (99.6%) provided by the past European Union evaluations to a sensitivity of 50%, more consistent with published data obtained under field conditions in infected goat populations. It was concluded that during the period 2016-2023, Slovenia has tested annually a sufficient number of ovine and caprine animals over 18 months of age, sourced from the NSHC and SHC populations, to ensure a 95% level of confidence of detecting CS if it is present in that population at a prevalence rate exceeding 0.1%, assuming a test sensitivity of 90% or above. The same holds for the years 2016, 2021 and 2023, assuming a test sensitivity of at least 80%. Based on the proposed number of samples for 2024 and future years, Slovenia would continue to meet the testing requirements assuming a test sensitivity of at least 80%.

Scrapie versus Chronic Wasting Disease in White-Tailed Deer.

White-tailed deer are susceptible to scrapie (WTD scrapie) after oronasal inoculation with the classical scrapie agent from sheep. Deer affected by WTD scrapie are difficult to differentiate from deer infected with chronic wasting disease (CWD). To assess the transmissibility of the WTD scrapie agent and tissue phenotypes when further passaged in white-tailed deer, we oronasally inoculated wild-type white-tailed deer with WTD scrapie agent. We found that WTD scrapie and CWD agents were generally similar, although some differences were noted. The greatest differences were seen in bioassays of cervidized mice that exhibited significantly longer survival periods when inoculated with WTD scrapie agent than those inoculated with CWD agent. Our findings establish that white-tailed deer are susceptible to WTD scrapie and that the presence of WTD scrapie agent in the lymphoreticular system suggests the handling of suspected cases should be consistent with current CWD guidelines because environmental shedding may occur.

Characterisation of European Field Goat Prion Isolates in Ovine PrP Overexpressing Transgenic Mice (Tgshp IX) Reveals Distinct Prion Strains.

After the detection of bovine spongiform encephalopathy (BSE), and a zoonotic transmissible spongiform encephalopathy (TSE) caused by the pathological prion protein (PrPSc) in two goats, the investigation of goat prions became of greater interest. Therefore, a broad collection of European goat TSE isolates, including atypical scrapie, CH1641 and goat BSE as reference prion strains were biochemically characterised and subsequently inoculated into seven rodent models for further analysis (already published results of this comprehensive study are reviewed here for comparative reasons). We report here the histopathological and immunohistochemical data of this goat TSE panel, obtained after the first passage in Tgshp IX (tg-shARQ) mice, which overexpress the ovine prion protein. In addition to the clear-cut discrimination of all reference prion strains from the classical scrapie (CS) isolates, we were further able to determine three categories of CS strains. The investigation further indicates the occurrence of sub-strains that slightly resemble distant TSE strains, such as BSE or CH1641, reinforcing the theory that CS is not a single strain but a mixture of sub-strains, existing at varying extents in one isolate. This study further proved that Tgshp IX is a potent and reliable tool for the in-depth characterisation of prion strains.

Towards spatial predictions of disease transmission risk: classical scrapie spill-over from domestic small ruminants to wild cervids

Towards spatial predictions of disease transmission risk: classical scrapie spill-over from domestic small ruminants to wild cervids

Sleep disturbance in clinical and preclinical scrapie-infected sheep measured by polysomnography

Neurodegenerative diseases are characterised by neuronal loss and abnormal deposition of pathological proteins in the nervous system. Among the most common neurodegenerative diseases are Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease and transmissible spongiform encephalopathies (TSEs). Sleep and circadian rhythm disturbances are one of the most common symptoms in patients with neurodegenerative diseases. Currently, one of the main objectives in the study of TSEs is to try to establish an early diagnosis, as clinical signs do not appear until the damage to the central nervous system is very advanced, which prevents any therapeutic approach. In this paper, we provide the first description of sleep disturbance caused by classical scrapie in clinical and preclinical sheep using polysomnography compared to healthy controls. Fifteen sheep classified into three groups, clinical, preclinical and negative control, were analysed. The results show a decrease in total sleep time as the disease progresses, with significant changes between control, clinical and pre-clinical animals. The results also show an increase in sleep fragmentation in clinical animals compared to preclinical and control animals. In addition, sheep with clinical scrapie show a total loss of Rapid Eye Movement sleep (REM) and alterations in Non Rapid Eyes Movement sleep (NREM) compared to control sheep, demonstrating more shallow sleep. Although further research is needed, these results suggest that prion diseases also produce sleep disturbances in animals and that polysomnography could be a diagnostic tool of interest in clinical and preclinical cases of prion diseases.

Temporal serum neurofilament light chain concentrations in sheep inoculated with the agent of classical scrapie.

Neurofilament light chain (Nf-L) has been used to detect neuroaxonal damage in the brain caused by physical injury or disease. The purpose of this study was to determine if serum Nf-L could be used as a biomarker for pre-symptomatic detection of scrapie in sheep. Four sheep with prion protein genotype AVQQ were intranasally inoculated with the classical scrapie strain x124. Blood was collected every 4 weeks until 44 weeks post-inoculation, at which point weekly collection commenced. Serum was analyzed using single molecule array (Quanterix SR-X) to evaluate Nf-L concentrations. Scrapie was confirmed in each sheep by testing homogenized brainstem at the level of the obex with a commercially available enzyme immunoassay. Increased serum Nf-L concentrations were identified above the determined cutoff during the last tenth of the respective incubation period for each sheep. Throughout the time course study, PrPSc accumulation was not detected antemortem by immunohistochemistry in rectal tissue at any timepoint for any sheep. RT-QuIC results were inconsistently positive throughout the timepoints tested for each sheep; however, each sheep had at least one timepoint detected positive. When assessing serum Nf-L utility using receiver operator characteristic curves against different clinical parameters, such as asymptomatic and symptomatic (pruritus or neurologic signs), results showed that Nf-L was most useful at being an indicator of disease only late in disease progression when neurologic signs were present. Serum Nf-L concentrations in the cohort of sheep increased as disease progressed; however, serum Nf-L did not increase during the presymptomatic window. The levels increased substantially throughout the final 10% of the animals' scrapie incubation period when other clinical signs were present. Serum Nf-L is not a reliable biomarker for pre-clinical detection of scrapie.

Change in the molecular properties of CH1641 prions after transmission to wild-type mice: Evidence for a single strain.

CH1641 was discovered in 1970 as a scrapie isolate that was unlike all other classical strains of scrapie isolated so far. We performed bio-assays of CH1641 in mice in order to further characterise this specific isolate. We inoculated the original CH1641 isolate into ovine and bovine prion protein (PrP) transgenic mice as well as wild-type mice. In addition, we performed cross- and back passages between the various mouse lines to examine if one identical prion strain was isolated in all mouse lines or whether multiple prion strains exist in CH1641. We report the first successful transmission of CH1641 to wild-type RIII mice and via RIII mice to wild-type VM mice. Unexpectedly, analysis of the protease-resistant prion protein (PrPres ) in wild-type mice showed a classical scrapie banding pattern differing from the banding pattern of the original CH1641 isolate. Cross- and back passages of CH1641 between the various mouse lines confirmed that the same prion strain had been isolated in all mouse lines. The CH1641 isolate consists of a single prion strain but its molecular banding pattern of PrPres differs between wild-type mice and PrP transgenic mice. Consequently, molecular banding patterns of PrPres should be used with caution in strain typing since they do not solely depend on the properties of the prion strain but also on the host prion protein.

Аnalysis of the imports of Ile de France animals in Bulgaria, 2005-2023

The meat sheep breed Ile-de-France was introduced from France to Bulgaria more than 50 years ago. However, the most imports took place in the recent 20 years and especially after the establishment in 2005 of a breeding association for this breed in Bulgaria. In this study, an attempt to analyse and review the imports from France in the last 18 years was made. It was based on the data about the imported animals provided by the Association for breeding of Ile-de-France sheep in Bulgaria. These animals were selected for import not only on the quality of their parents, but also on their genetic predisposal to classical Scrapie. As a result, most of the animals with known prion protein gene genotypes were of the preferred, low risk one. Within the parents, for which data was available, 34% of the sires were ranked as improvers of growth qualities, and 45% of the dams as mothers of sires. The animals were raised in similar climatic conditions in both countries. The animal with most progeny in the herdbook was also imported one, having 163 records as a sire. The continuous import of low risk genotype animals should have positive impact on the resistance of the local population against Scrapie. As there are also Ile-de-France animals raised in Bulgaria, it might be beneficial to monitor the genetic diversity of prion protein gene in the local population.

Disease phenotype of classical sheep scrapie is changed upon experimental passage through white-tailed deer.

Prion agents occur in strains that are encoded by the structure of the misfolded prion protein (PrPSc). Prion strains can influence disease phenotype and the potential for interspecies transmission. Little is known about the potential transmission of prions between sheep and deer. Previously, the classical US scrapie isolate (No.13-7) had a 100% attack rate in white-tailed deer after oronasal challenge. The purpose of this study was to test the susceptibility of sheep to challenge with the scrapie agent after passage through white-tailed deer (WTD scrapie). Lambs of various prion protein genotypes were oronasally challenged with WTD scrapie. Sheep were euthanized and necropsied upon development of clinical signs or at the end of the experiment (72 months post-inoculation). Enzyme immunoassay, western blot, and immunohistochemistry demonstrated PrPSc in 4 of 10 sheep with the fastest incubation occurring in VRQ/VRQ sheep, which contrasts the original No.13-7 inoculum with a faster incubation in ARQ/ARQ sheep. Shorter incubation periods in VRQ/VRQ sheep than ARQ/ARQ sheep after passage through deer was suggestive of a phenotype change, so comparisons were made in ovinized mice and with sheep with known strains of classical sheep scrapie: No. 13-7 and x-124 (that has a more rapid incubation in VRQ/VRQ sheep). After mouse bioassay, the WTD scrapie and x-124 isolates have similar incubation periods and PrPSc conformational stability that are markedly different than the original No. 13-7 inoculum. Furthermore, brain tissues of sheep with WTD scrapie and x-124 scrapie have similar patterns of immunoreactivity that are distinct from sheep with No. 13-7 scrapie. Multiple lines of evidence suggest a phenotype switch when No. 13-7 scrapie prions are passaged through deer. This represents one example of interspecies transmission of prions resulting in the emergence or selection of new strain properties that could confound disease eradication and control efforts.

Diagnosis in Scrapie: Conventional Methods and New Biomarkers.

Scrapie, a naturally occurring prion disease affecting goats and sheep, comprises classical and atypical forms, with classical scrapie being the archetype of transmissible spongiform encephalopathies. This review explores the challenges of scrapie diagnosis and the utility of various biomarkers and their potential implications for human prion diseases. Understanding these biomarkers in the context of scrapie may enable earlier prion disease diagnosis in humans, which is crucial for effective intervention. Research on scrapie biomarkers bridges the gap between veterinary and human medicine, offering hope for the early detection and improved management of prion diseases.

The European Union summary report on surveillance for the presence of transmissible spongiform encephalopathies (TSE) in 2022.

This report presents the results of surveillance on transmissible spongiform encephalopathies (TSE) in cattle, sheep, goats, cervids and other species, and genotyping in sheep and goats, carried out in 2022 by 27 Member States (MS, EU27), the United Kingdom (in respect of Northern Ireland [XI]) and other eight non-EU reporting countries: Bosnia and Herzegovina, Iceland, Montenegro, North Macedonia, Norway, Serbia, Switzerland and Türkiye. In total, 977,008 cattle were tested by EU27 and XI (-4.3%, compared with 2021), and 52,395 cattle by eight non-EU reporting countries, with one case of H-BSE in France. In total, 295,145 sheep and 109,074 goats were tested in the EU27 and XI (-5.2% and -7.9%, respectively, compared to 2021). In the other non-EU reporting countries, 25,535 sheep and 633 goats were tested. In sheep, 557 cases of scrapie were reported by 17 MS and XI: 480 classical scrapie (CS) by five MS (93 index cases [IC] with genotypes of susceptible groups in 97.6% of the cases), 77 atypical scrapie (AS) (76 IC) by 14 MS and XI. In the other non-EU reporting countries, Norway reported 16 cases of ovine AS. Ovine random genotyping was reported by eight MS and genotypes of susceptible groups accounted for 7.3%. In goats, 224 cases of scrapie were reported, all from EU MS: 216 CS (42 IC) by six MS, and 8 AS (8 IC) by four MS. In Cyprus, two cases of CS were reported in goats carrying the heterozygous DN146 allele. In total, 3202 cervids were tested for chronic wasting disease by 10 MS. One wild European moose tested positive in Finland. Norway tested 17,583 cervids with two European moose, one reindeer and one red deer positive. In total, 154 animals from four other species tested negative in Finland.

Characterization of the First Case of Classical Scrapie in a Sheep in Tunisia

Classical scrapie is a contagious prion disease of sheep and goats. It is endemic in many countries in Europe, North America, and Asia. In Africa, imported scrapie cases have been described in South Africa and Kenia in the past. More recently, several cases have been reported from different regions of Libya, based on clinical signs and histological lesions. Here, we report the results of thorough investigations carried out on a suspect case of scrapie in a 6-year-old Barbarine sheep, born, and bred in Tunisia, showing behavioral changes, weight loss, itching, skin lesions, wool loss, and motor incoordination. Histopathology and immunohistochemistry revealed spongiform change in several brain areas with associated pathological prion protein deposition. Western blotting confirmed the diagnosis and showed a classical scrapie-like molecular pattern of PrPres, different from atypical scrapie and bovine spongiform encephalopathy (BSE) in small ruminants. Sequence analysis of the prion protein gene showed that the animal carried the ARQ/ARQ genotype, one of the most susceptible to classical scrapie. The inoculation of sheep brain homogenate in a susceptible rodent model proved the experimental transmissibility of the disease. These results demonstrate the circulation of classical scrapie in Tunisia and confirm its presence in North Africa, indicating the need to improve epidemiological surveillance and diagnostic capacity for prion diseases in the region.

Evaluation of the application of the Czech Republic to be recognised as having a negligible risk of classical scrapie.

The Czech Republic submitted a request to the European Commission to be recognised as a Member State with negligible risk of classical scrapie. EFSA has been asked to assess if the Czech Republic in its application has demonstrated for a period of at least 7 years (2015-2021) and proposed for the future, that a sufficient number of ovine and caprine animals over 18 months of age, representative of slaughtered, culled or found dead on farm animals, have been and will continue to be tested annually to provide a 95% level of confidence of detecting classical scrapie if it is present in that population at a prevalence rate exceeding 0.1%. A risk-based approach using stochastic scenario-tree modelling accounting for surveillance stream and species was applied. There is still a lack of data on the actual performance of the approved tests under field conditions, especially in sheep. Therefore, alternative scenarios were explored extending the range from the sensitivity provided by the past European Union evaluations of diagnostic screening tests to a sensitivity of 50%, consistent with published data obtained under field conditions in infected goat populations. Using data provided by the Czech Republic for 2015-2022, the estimated parameters of the scenario-tree model, the range of values of diagnostic sensitivity and applying the criterion for the 95% confidence level, it is concluded that the Czech Republic has tested annually a sufficient number of small ruminants to meet the requirement, for all combinations of years and diagnostic sensitivity scenarios except for 60% diagnostic sensitivity in 2021 and 2022, and 50% in 2015, 2016 and 2018-2022. Based on the proposed number of samples to be tested in 2023 and future years, the Czech Republic would test a sufficient number of animals to meet the requirement for all combinations of diagnostic sensitivity, except for the 50% scenario.

Inter- and intra-species conversion efficacies of Norwegian prion isolates estimated by serial protein misfolding cyclic amplification

Prion diseases, including chronic wasting disease (CWD) in cervids, are fatal neurodegenerative disorders caused by the misfolding of cellular prion proteins. CWD is known to spread among captive and free-ranging deer in North America. In 2016, an outbreak of contagious CWD was detected among wild reindeer in Norway, marking the first occurrence of the disease in Europe. Additionally, new sporadic forms of CWD have been discovered in red deer in Norway and moose in Fennoscandia. We used serial protein misfolding cyclic amplification to study the ability of Norwegian prion isolates from reindeer, red deer, and moose (two isolates), as well as experimental classical scrapie from sheep, to convert a panel of 16 brain homogenates (substrates) from six different species with various prion protein genotypes. The reindeer CWD isolate successfully converted substrates from all species except goats. The red deer isolate failed to convert sheep and goat substrates but exhibited amplification in all cervid substrates. The two moose isolates demonstrated lower conversion efficacies. The wild type isolate propagated in all moose substrates and in the wild type red deer substrate, while the other isolate only converted two of the moose substrates. The experimental classical scrapie isolate was successfully propagated in substrates from all species tested. Thus, reindeer CWD and classical sheep scrapie isolates were similarly propagated in substrates from different species, suggesting the potential for spillover of these contagious diseases. Furthermore, the roe deer substrate supported conversion of three isolates suggesting that this species may be vulnerable to prion disease.

Predicting Risk Areas of Classical Scrapie in China Based on Environmental Suitability

Classical scrapie is a transmissible spongiform encephalopathy that attacks the central nervous system of sheep and goats. Since its discovery in the 18th century, the disease has caused enormous economic losses and public health impacts in continental Europe. In the late 20th century, classical scrapie began to spread to places, such as Asia and the Americas, becoming a disease of global concern. In this study, based on prion occurrence records and high-resolution environmental layers, a risk assessment of classical scrapie in China was performed using a maximum entropy model. The model achieved an area under the curve value of 0.906 (95% confidence interval, 0.0883–0.0929). Sheep distribution density, road density, goat distribution density, minimum temperature of the coldest month, port density, and precipitation of the driest quarter were identified as important factors affecting the occurrence of classical scrapie. The risk map showed that potential high-risk areas in China were mainly located in Northeast China, North China, and Northwest China. This study can provide a valuable reference for the prevention of classical scrapie in China. According to the environmental variables and risk areas of classical scrapie, implementing monitoring and early warning measures in these areas is recommended to reduce the possibility of classical scrapie occurrence and transmission.

Polymorphism of prion protein gene (PRNP) in Nigerian sheep

ABSTRACT Polymorphism of the prion protein gene (PRNP) gene determines an animal’s susceptibility to scrapie. Three polymorphisms at codons 136, 154, and 171 have been linked to classical scrapie susceptibility, although many variants of PRNP have been reported. However, no study has investigated scrapie susceptibility in Nigerian sheep from the drier agro-climate zones. In this study, we aimed to identify PRNP polymorphism in nucleotide sequences of 126 Nigerian sheep by comparing them with public available studies on scrapie-affected sheep. Further, we deployed Polyphen-2, PROVEAN, and AMYCO analyses to determine the structure changes produced by the non-synonymous SNPs. Nineteen (19) SNPs were found in Nigerian sheep with 14 being non-synonymous. Interestingly, one novel SNP (T718C) was identified. There was a significant difference (P < 0.05) in the allele frequencies of PRNP codon 154 between sheep in Italy and Nigeria. Based on the prediction by Polyphen-2, R154H was probably damaging while H171Q was benign. Contrarily, all SNPs were neutral via PROVEAN analysis while two haplotypes (HYKK and HDKK) had similar amyloid propensity of PRNP with resistance haplotype in Nigerian sheep. Our study provides valuable information that could be possibly adopted in programs targeted at breeding for scrapie resistance in sheep from tropical regions.

Genetic variability of the prion protein gene in Indonesian goat breeds

Scrapie is a naturally occurring transmissible spongiform encephalopathy in sheep and goats. Resistance or susceptibility of small ruminants to classical scrapie is influenced by polymorphisms in the prion protein gene (PRNP). PRNP variability in Indonesian indigenous goat breeds has not been investigated so far and therefore was the goal of this study. Sanger sequencing of the PRNP gene coding region in 72 goats of the seven Indonesian breeds Kacang, Gembrong, Samosir, Kejobong, Benggala, Jawarandu, and Peranakan Etawah revealed three amino acid substitutions, namely W102G, H143R, and S240P. Some silent mutations were also found at codons 42 (a/g), 138 (c/t), and 179 (g/t). The PRNP alleles K222 and D/S146 known to have significant protective effects on resistance to classical scrapie in goats were not detected. The allele R143, which may have a moderate protective effect, had a frequency of 12% among the analyzed Indonesian goat breeds. While R143 was missing in Kacang and Benggala, its frequency was highest in the breed Gembrong (32%). No scrapie cases have been reported in Indonesia until now. However, in the case that selection for protective PRNP variants would become a breeding goal, the analyzed breeds will not be very useful resources. Other goat breeds which are present in the country should be investigated regarding resistance to scrapie, too.

A Mass Spectrometry-Based Method of Quantifying the Contribution of the Lysine Polymorphism at Position 171 in Sheep PrP.

In sheep, the transmissibility and progression of scrapie, a sheep prion (PrPSc) disease, is strongly dependent upon specific amino acid polymorphisms in the natively expressed prion protein (PrPC). Sheep expressing PrPC with lysine (K) polymorphism at position 171 (K171) are partially resistant to oronasal dosing of classical sheep scrapie. In addition, scrapie infected sheep expressing the K171 polymorphism show a longer incubation period compared to sheep homozygous (glutamine (Q)) at position 171. Quantitating the amount of the K171 polymorphism in a sheep scrapie sample can provide important information on the composition of PrPSc. A tryptic peptide, 159R.YPNQVYYRPVDK.Y172, derived from the digestion of 171K recombinant PrP, was identified as an analyte peptide suitable for a multiple reaction monitoring-based analysis. This method, using 15N-labeled analogs and another internal peptide from the proteinase K-resistant core, permits the simultaneous quantitation of the total amount of PrP and the proportion of K171 polymorphism in the sample. Background molecules with similar retention times and transitions were present in samples from scrapie-infected sheep. Proteinase K digestion followed by ultracentrifugation-based isolation or phosphotungstic acid-based isolation were employed to minimize the contribution of those background molecules, making this approach suitable for quantitating the amount of the K171 polymorphism in heterozygous scrapie infected sheep.

Evaluation of Resistance and Susceptibility to Prion Diseases in Pelibuey Sheep from Mexico

Abstract Transmissible spongiform encephalopathies (TSEs) are a group of neurodegenerative diseases with a chronic and fatal course, which are caused by a misfolded form of the cellular prion protein that is encoded by the host. The purpose of this work was to evaluate the resistance and genetic susceptibility to prion diseases in Pelibuey sheep from Mexico. The sequences of 99 Pelibuey sheep from the central and southwestern regions of Mexico were analyzed to determine the polymorphisms related to resistance and genetic susceptibility to scrapie, the Hardy-Weinberg equilibrium test and the D-Tajima test was used to identify the effect of evolutionary forces on the PRNP gene. Twelve non-synonymous polymorphisms Q101R, M112T, A116P, G127A, A136V, M137T, L141F, H143R, R154H, Q171R, Q171H, N176K were detected, in addition two synonymous substitutions 231R (agg/cgg) and 237L (ctc/ctg) were found. As a result of the sequence analysis, the ARR allele was not under the Hardy-Weinberg equilibrium, indicating that there is an evolutionary force at work, and the D-Tajima suggest the existence of purifying genetic selection. In conclusion, Pelibuey sheep exhibit genotypes for the PRNP gene that make them resistant to developing classic scrapie; at least 98% of the population is a carrier of an allele related to scrapie resistance; while for atypical scrapie there is a very high probability that an outbreak occurred in the herds, since the ARQ allele in combination with the L substitution at codon 141 confers susceptibility to carrier sheep.

Bona fide atypical scrapie faithfully reproduced for the first time in a rodent model

Atypical Scrapie, which is not linked to epidemics, is assumed to be an idiopathic spontaneous prion disease in small ruminants. Therefore, its occurrence is unlikely to be controlled through selective breeding or other strategies as it is done for classical scrapie outbreaks. Its spontaneous nature and its sporadic incidence worldwide is reminiscent of the incidence of idiopathic spontaneous prion diseases in humans, which account for more than 85% of the cases in humans. Hence, developing animal models that consistently reproduce this phenomenon of spontaneous PrP misfolding, is of importance to study the pathobiology of idiopathic spontaneous prion disorders. Transgenic mice overexpressing sheep PrPC with I112 polymorphism (TgShI112, 1–2 × PrP levels compared to sheep brain) manifest clinical signs of a spongiform encephalopathy spontaneously as early as 380 days of age. The brains of these animals show the neuropathological hallmarks of prion disease and biochemical analyses of the misfolded prion protein show a ladder-like PrPres pattern with a predominant 7–10 kDa band. Brain homogenates from spontaneously diseased transgenic mice were inoculated in several models to assess their transmissibility and characterize the prion strain generated: TgShI112 (ovine I112 ARQ PrPC), Tg338 (ovine VRQ PrPC), Tg501 (ovine ARQ PrPC), Tg340 (human M129 PrPC), Tg361 (human V129 PrPC), TgVole (bank vole I109 PrPC), bank vole (I109I PrPC), and sheep (AHQ/ARR and AHQ/AHQ churra-tensina breeds). Our analysis of the results of these bioassays concludes that the strain generated in this model is indistinguishable to that causing atypical scrapie (Nor98). Thus, we present the first faithful model for a bona fide, transmissible, ovine, atypical scrapie prion disease.