Review: Update on Classical and Atypical Scrapie in Sheep and Goats

Greenlee, Justin J.

doi:10.1177/0300985818794247

Cited by 43 publications

(55 citation statements)

References 171 publications

(235 reference statements)

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“…More than 50 polymorphisms in the goat prion protein-coding gene were reported worldwide 25 . A recent study on Ethiopian goat population reported six variants in Western Highland, Central Highland, and Long Eared Somali breeds of Ethiopia www.nature.com/scientificreports www.nature.com/scientificreports/ Silent substitution at codon S138 was observed in 29% of Afar, 31% of Arsi-Bale(present study) and 15% of Tanzanian goat breeds 23 .…”

Section: Discussionmentioning

confidence: 99%

Novel Variations in Native Ethiopian Goat breeds PRNP Gene and Their Potential Effect on Prion Protein Stability

Teferedegn

Yaman

Ün

2020

Sci Rep

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Scrapie is a lethal neurodegenerative disease of sheep and goats caused by the misfolding of the prion protein. Variants such as M142, D145, S146, H154, Q211, and K222 were experimentally found to increase resistance or extend scrapie incubation period in goats. We aimed to identify polymorphisms in the Afar and Arsi-Bale goat breeds of Ethiopia and computationally assess the effect of variants on prion protein stability. In the present study, four non-synonymous novel polymorphisms G67S, W68R, G69D, and R159H in the first octapeptide repeat and the highly conserved C-terminus globular domain of goat PrP were detected. The resistant genotype, S146, was detected in >50% of the present population. The current study population showed a genetic diversity in Ethiopian goat breeds. In the insilico analysis, the R68 variant was predicted to increase stability while S67, D69, and H159 decrease the stability of prion protein. The new variants in the octapeptide repeat motif were predicted to decrease amyloidogenicity but H159 increased the hotspot sequence amyloidogenic propensity. These novel variants could be the source of conformational flexibility that may trigger the gain or loss of function by prion protein. Further experimental study is required to depict the actual effects of variants on prion protein stability. Prion diseases are lethal neurodegenerative disease of humans and animals caused by the misfolding of prion protein 1. Despite being rare, the diseases are lethal and have resulted in huge animal loss over a course of time in several countries 2. The oldest prion disease is scrapie that affects small ruminants 3,4. Though the exact pathomechanism is not yet known, predisposing genetic variants have been documented in different species 5. A wide range of polymorphisms have been identified in goats either as protective or susceptible alleles. A recent review reported the presence of more than 50 polymorphisms in goat prion protein-coding gene (PRNP) 6. Among the variants, G127S, M142I, H143R, N146S, R154H, Q222K, and S240P are the most common substitutions worldwide 7,8. Similarly, R139S in Algeria 9 , A116V in Tanzania 10 , G134E and Q163P in Turkey 11 and G127A and T193I in Ethiopia 12 were novel (at the time of the report) substitutions discovered in the respective area of study. Alleles such as M142, D145, S146, H154, Q211, and K222 were experimentally found to either extend scrapie incubation period or increase resistance 8,13-16. Experimental studies reported the link between sequence variation in the functional domains of prion protein and scrapie disease development 17,18. Substitutions in the palindrome and glycine-rich motifs were identified to affect amyloid fibril formation 19. Although the C terminal globular domain is often involved in the PrP c to PrP Sc conversion process, octapeptide repeat regions are also known to influence the structural dynamics of prion protein. Insertion or deletion of octapeptide repeat for example, induce disease phenotypes 20. According to the FAOSTAT 2017 report, 3...

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Section: Discussionmentioning

confidence: 99%

Novel Variations in Native Ethiopian Goat breeds PRNP Gene and Their Potential Effect on Prion Protein Stability

Teferedegn

Yaman

Ün

2020

Sci Rep

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“…Finally, in this study all samples were taken from sheep carrying the same PRNP genotype (ARQ/ARQ) and it is critical to extend this analysis to blood samples taken from other genotypes. It is well established that PRNP genotypes in sheep influence susceptibility to scrapie and likely determine different clinical and pathological phenotypes [39].…”

Section: Discussionmentioning

confidence: 99%

Neurofilaments in blood is a new promising preclinical biomarker for the screening of natural scrapie in sheep

et al. 2019

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Scrapie is a fatal neurodegenerative disease of sheep and goats belonging to the group of Transmissible Spongiform Encephalopathy or prion diseases. The EU has adopted mandatory measures for scrapie surveillance to safeguard public and animal health because it is highly contagious and might decimate all genetic susceptible animals in affected flocks. Definite diagnosis of scrapie relies on the detection of the pathological prion protein in brain tissues and there are still no blood biomarkers available for making diagnosis in living animals that can be used for the screening of sheep in scrapie-affected flocks. Neurofilament light (NfL) protein, a valid biomarker for neuronal and axonal damages, can now be easily measured in blood by the ultra-sensitive single molecule array (Simoa) technology. Recent work reported that serum NfL is increased in neurodegenerative diseases, including human prion diseases, but no data are available for scrapie or other animal prion diseases. Here, we found that the median serum NfL concentration in scrapie animals (56.2, IQR 42.2–84.8, n = 9) was more than 15 times higher (p = 0.00084) than that found in control samples (3.4, IQR 3.0–26.3, n = 11). Moreover, serum NfL concentration in scrapie sheep with clinical signs (n = 2; 75.3, 15.7 pg/ml) did not significantly (p = 0.541; t-test) differ from scrapie animals without clinical signs (n = 7; 61.0, 10.7 pg/ml). The receiver operating characteristic (ROC) curve analysis estimated the cut-off value of 31 pg/ml serum NfL for distinguishing scrapie-infected sheep from controls. The application of this cut-off value gives an accuracy of the test of 95% (percent error of 5.23%). These data indicate that the Simoa test for serum NfL might be a useful screening method for detecting preclinical scrapie in living sheep. Finally, the preliminary data reported here need confirmation in large and more structured studies.

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“…Prion diseases are a group of fatal and infectious neurodegenerative disorders that include Creutzfeldt–Jacob disease in humans, bovine spongiform encephalopathy in cattle, scrapie in sheep and goat, and chronic wasting disease in cervids. Disease manifestation in human prion disorders can be sporadic, familial, or acquired by infection ( 1 – 5 ), whereas in animals acquired prion diseases prevail ( 6 – 9 ). Pathological hallmarks of prion diseases are vacuolation caused by neuronal death, PrP Sc plaque deposition, astrogliosis, and spongiform degeneration ( 10 ).…”

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confidence: 99%

An astrocyte cell line that differentially propagates murine prions

Tahir

Abdulrahman

Abdelaziz

et al. 2020

Journal of Biological Chemistry

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Prion diseases are fatal infectious neurodegenerative disorders in human and animals caused by misfolding of the cellular prion protein (PrPC) into the pathological isoform PrPSc. Elucidating the molecular and cellular mechanisms underlying prion propagation may help to develop disease interventions. Cell culture systems for prion propagation have greatly advanced molecular insights into prion biology, but translation of in vitro to in vivo findings is often disappointing. A wider range of cell culture systems might help overcome these shortcomings. Here, we describe an immortalized mouse neuronal astrocyte cell line (C8D1A) that can be infected with murine prions. Both PrPC protein and mRNA levels in astrocytes were comparable to those in neuronal and nonneuronal cell lines permitting persistent prion infection. We challenged astrocytes with three mouse-adapted prion strains (22L, RML, and ME7) and cultured them for six passages. Immunoblotting results revealed that the astrocytes propagated 22L prions well over all six passages, whereas ME7 prions did not replicate, and RML prions only very weakly after five passages. Immunofluorescence analysis indicated similar results for PrPSc. Interestingly, when we used prion conversion activity as a read-out in real-time quaking-induced conversion (RT-QuIC) assays with RML-infected cell lysates, we observed a strong signal over all six passages, comparable to that for 22L-infected cells. These data indicate that the C8D1A cell line is permissive to prion infection. Moreover, the propagated prions differed in conversion and proteinase K–resistance levels in these astrocytes. We propose that the C8D1A cell line could be used to decipher prion strain biology.

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Review: Update on Classical and Atypical Scrapie in Sheep and Goats

Cited by 43 publications

References 171 publications

Novel Variations in Native Ethiopian Goat breeds PRNP Gene and Their Potential Effect on Prion Protein Stability

Novel Variations in Native Ethiopian Goat breeds PRNP Gene and Their Potential Effect on Prion Protein Stability

Neurofilaments in blood is a new promising preclinical biomarker for the screening of natural scrapie in sheep

An astrocyte cell line that differentially propagates murine prions

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