scholarly journals Significant differences in incubation times in sheep infected with bovine spongiform encephalopathy result from variation at codon 141 in the PRNP gene

2012 ◽  
Vol 93 (12) ◽  
pp. 2749-2756 ◽  
Author(s):  
Boon Chin Tan ◽  
Anthony R. Alejo Blanco ◽  
E. Fiona Houston ◽  
Paula Stewart ◽  
Wilfred Goldmann ◽  
...  
Keyword(s):  
Amino Acid ◽  
Bovine Spongiform Encephalopathy ◽  
Prion Protein ◽  
Protein Misfolding ◽  
Prnp Gene ◽  
Brain Homogenate ◽  
Spongiform Encephalopathy ◽  
Direct Effects ◽  
Prion Infection ◽  
Incubation Periods

The susceptibility of sheep to prion infection is linked to variation in the PRNP gene, which encodes the prion protein. Common polymorphisms occur at codons 136, 154 and 171. Sheep which are homozygous for the A136R154Q171 allele are the most susceptible to bovine spongiform encephalopathy (BSE). The effect of other polymorphisms on BSE susceptibility is unknown. We orally infected ARQ/ARQ Cheviot sheep with equal amounts of BSE brain homogenate and a range of incubation periods was observed. When we segregated sheep according to the amino acid (L or F) encoded at codon 141 of the PRNP gene, the shortest incubation period was observed in LL141 sheep, whilst incubation periods in FF141 and LF141 sheep were significantly longer. No statistically significant differences existed in the expression of total prion protein or the disease-associated isoform in BSE-infected sheep within each genotype subgroup. This suggested that the amino acid encoded at codon 141 probably affects incubation times through direct effects on protein misfolding rates.

scholarly journals First Report of the Potential Bovine Spongiform Encephalopathy (BSE)-Related Somatic Mutation E211K of the Prion Protein Gene (PRNP) in Cattle

2020 ◽  
Vol 21 (12) ◽  
pp. 4246 ◽  
Author(s):  
Sae-Young Won ◽  
Yong-Chan Kim ◽  
Byung-Hoon Jeong
Keyword(s):  
Bovine Spongiform Encephalopathy ◽  
Prion Protein ◽  
Somatic Mutation ◽  
Prion Disease ◽  
In Silico ◽  
Somatic Mutations ◽  
Protein Gene ◽  
Prnp Gene ◽  
Spongiform Encephalopathy ◽  
Prion Protein Gene

Bovine spongiform encephalopathy (BSE) is a prion disease characterized by spongiform degeneration and astrocytosis in the brain. Unlike classical BSE, which is caused by prion-disease-contaminated meat and bone meal, the cause of atypical BSE has not been determined. Since previous studies have reported that the somatic mutation in the human prion protein gene (PRNP) has been linked to human prion disease, the somatic mutation of the PRNP gene was presumed to be one cause of prion disease. However, to the best of our knowledge, the somatic mutation of this gene in cattle has not been investigated to date. We investigated somatic mutations in a total of 58 samples, including peripheral blood; brain tissue including the medulla oblongata, cerebellum, cortex, and thalamus; and skin tissue in 20 individuals from each breed using pyrosequencing. In addition, we estimated the deleterious effect of the K211 somatic mutation on bovine prion protein by in silico evaluation tools, including PolyPhen-2 and PANTHER. We found a high rate of K211 somatic mutations of the bovine PRNP gene in the medulla oblongata of three Holsteins (10% ± 4.4%, 28% ± 2%, and 19.55% ± 3.1%). In addition, in silico programs showed that the K211 somatic mutation was damaging. To the best of our knowledge, this study is the first to investigate K211 somatic mutations of the bovine PRNP gene that are associated with potential BSE progression.

scholarly journals Prion Type-Dependent Deposition ofPRNPAllelic Products in Heterozygous Sheep

2015 ◽  
Vol 90 (2) ◽  
pp. 805-812 ◽  
Author(s):  
J. P. M. Langeveld ◽  
J. G. Jacobs ◽  
N. Hunter ◽  
L. J. M. van Keulen ◽  
F. Lantier ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequence ◽  
Bovine Spongiform Encephalopathy ◽  
Prion Protein ◽  
Transmissible Spongiform Encephalopathy ◽  
Infected Sheep ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathy ◽  
Sequence Variants ◽  
Spongiform Encephalopathies

ABSTRACTSusceptibility or resistance to prion infection in humans and animals depends on single prion protein (PrP) amino acid substitutions in the host, but the agent's modulating role has not been well investigated. Compared to disease incubation times in wild-type homozygous ARQ/ARQ (where each triplet represents the amino acids at codons 136, 154, and 171, respectively) sheep, scrapie susceptibility is reduced to near resistance in ARR/ARR animals while it is strongly enhanced in VRQ/VRQ carriers. Heterozygous ARR/VRQ animals exhibit delayed incubation periods. In bovine spongiform encephalopathy (BSE) infection, the polymorphism effect is quite different although the ARR allotype remains the least susceptible. In this study, PrP allotype composition in protease-resistant prion protein (PrPres) from brain of heterozygous ARR/VRQ scrapie-infected sheep was compared with that of BSE-infected sheep with a similar genotype. A triplex Western blotting technique was used to estimate the two allotype PrP fractions in PrPresmaterial from BSE-infected ARR/VRQ sheep. PrPresin BSE contained equimolar amounts of VRQ- and ARR-PrP, which contrasts with the excess (>95%) VRQ-PrP fraction found in PrP in scrapie. This is evidence that transmissible spongiform encephalopathy (TSE) agent properties alone, perhaps structural aspects of prions (such as PrP amino acid sequence variants and PrP conformational state), determine the polymorphic dependence of the PrPresaccumulation process in prion formation as well as the disease-associated phenotypic expressions in the host.IMPORTANCETransmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative and transmissible diseases caused by prions. Amino acid sequence variants of the prion protein (PrP) determine transmissibility in the hosts, as has been shown for classical scrapie in sheep. Each individual produces a separate PrP molecule from its two PrP gene copies. Heterozygous scrapie-infected sheep that produce two PrP variants associated with opposite scrapie susceptibilities (136V-PrP variant, high; 171R-PrP variant, very low) contain in their prion material over 95% of the 136V PrP variant. However, when these sheep are infected with prions from cattle (bovine spongiform encephalopathy [BSE]), both PrP variants occur in equal ratios. This shows that the infecting prion type determines the accumulating PrP variant ratio in the heterozygous host. While the host's PrP is considered a determining factor, these results emphasize that prion structure plays a role during host infection and that PrP variant involvement in prions of heterozygous carriers is a critical field for understanding prion formation.

scholarly journals Strain-Dependent Prion Infection in Mice Expressing Prion Protein with Deletion of Central Residues 91–106

2020 ◽  
Vol 21 (19) ◽  
pp. 7260
Author(s):  
Keiji Uchiyama ◽  
Hironori Miyata ◽  
Yoshitaka Yamaguchi ◽  
Morikazu Imamura ◽  
Mariya Okazaki ◽  
...  
Keyword(s):  
Prion Protein ◽  
Protein Misfolding ◽  
Prion Diseases ◽  
Cellular Prion Protein ◽  
Spongiform Encephalopathy ◽  
Dependent Manner ◽  
Prion Infection ◽  
Amplification Assay ◽  
The Brain ◽  
Strain Dependent

Conformational conversion of the cellular prion protein, PrPC, into the abnormally folded isoform, PrPSc, is a key pathogenic event in prion diseases. However, the exact conversion mechanism remains largely unknown. Transgenic mice expressing PrP with a deletion of the central residues 91–106 were generated in the absence of endogenous PrPC, designated Tg(PrP∆91–106)/Prnp0/0 mice and intracerebrally inoculated with various prions. Tg(PrP∆91–106)/Prnp0/0 mice were resistant to RML, 22L and FK-1 prions, neither producing PrPSc∆91–106 or prions in the brain nor developing disease after inoculation. However, they remained marginally susceptible to bovine spongiform encephalopathy (BSE) prions, developing disease after elongated incubation times and accumulating PrPSc∆91–106 and prions in the brain after inoculation with BSE prions. Recombinant PrP∆91-104 converted into PrPSc∆91–104 after incubation with BSE-PrPSc-prions but not with RML- and 22L–PrPSc-prions, in a protein misfolding cyclic amplification assay. However, digitonin and heparin stimulated the conversion of PrP∆91–104 into PrPSc∆91–104 even after incubation with RML- and 22L-PrPSc-prions. These results suggest that residues 91–106 or 91–104 of PrPC are crucially involved in prion pathogenesis in a strain-dependent manner and may play a similar role to digitonin and heparin in the conversion of PrPC into PrPSc.

scholarly journals Reduced susceptibility to bovine spongiform encephalopathy prions in transgenic mice expressing a bovine PrP with five octapeptide repeats

2007 ◽  
Vol 88 (6) ◽  
pp. 1842-1849 ◽  
Author(s):  
Alejandro Brun ◽  
Alfonso Gutiérrez-Adán ◽  
Joaquín Castilla ◽  
Belén Pintado ◽  
Fayna Díaz-San Segundo ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Bovine Spongiform Encephalopathy ◽  
Prion Protein ◽  
De Novo ◽  
Natural Source ◽  
Proteinase K ◽  
Spongiform Encephalopathy ◽  
Intracerebral Inoculation ◽  
Prion Infection ◽  
Cattle Breeds

In this work, transgenic (Tg) mice were generated expressing a bovine prion protein containing five octarepeats (BoPrP5OR-Tg). After intracerebral inoculation of bovine spongiform encephalopathy (BSE) inoculum, these mice suffered a BSE-like neuropathology but survived longer compared with homologous Tg mice expressing similar levels of a six octarepeat BoPrP protein (BoPrP6OR-Tg). De novo-generated five octarepeat (5OR) PrPSc showed no biochemical differences from 6OR-PrPSc, and the proteinase K-resistant core (PrPres) was biochemically indistinguishable from the 6OR counterpart. Lower susceptibility to BSE is suggested for BoPrP5OR-Tg mice, as they were not as efficient at replicating BSE prions from the same natural source inoculum as BoPrP6OR-Tg mice expressing similar PrPC levels. These results raise the possibility of selecting cattle breeds bearing the 5OR Prnp allele that are less susceptible to prion infection.

scholarly journals Detection of PrPSc in peripheral tissues of clinically affected cattle after oral challenge with bovine spongiform encephalopathy

2012 ◽  
Vol 93 (12) ◽  
pp. 2740-2748 ◽  
Author(s):  
Martin Franz ◽  
Martin Eiden ◽  
Anne Balkema-Buschmann ◽  
Justin Greenlee ◽  
Hermann Schatzl ◽  
...  
Keyword(s):  
Bovine Spongiform Encephalopathy ◽  
Protein Misfolding ◽  
Brain Homogenate ◽  
Diagnostic Methods ◽  
Spongiform Encephalopathy ◽  
Variant Form ◽  
Mesenteric Lymph Nodes ◽  
Tissue Samples ◽  
Peripheral Tissues ◽  
Resistant Disease

Bovine spongiform encephalopathy (BSE) is a fatal neurodegenerative prion disease that mainly affects cattle. Transmission of BSE to humans caused a variant form of Creutzfeldt–Jakob disease. Following infection, the protease-resistant, disease-associated isoform of prion protein (PrPSc) accumulates in the central nervous system and in other tissues. Many countries have defined bovine tissues that may contain prions as specified risk materials, which must not enter the human or animal food chains and therefore must be discarded. Ultrasensitive techniques such as protein misfolding cyclic amplification (PMCA) have been developed to detect PrPSc when present in minuscule amounts that are not readily detected by other diagnostic methods such as immunohistochemistry or Western blotting. This study was conducted to determine when and where PrPSc can be found by PMCA in cattle orally challenged with BSE. A total of 48 different tissue samples from four cattle infected orally with BSE at various clinical stages of disease were examined using a standardized PMCA protocol. The protocol used brain homogenate from bovine PrP transgenic mice (Tgbov XV) as substrate and three consecutive rounds of PMCA. Using this protocol, PrPSc was found in the brain, spinal cord, nerve ganglia, optic nerve and Peyer’s patches. The presence of PrPSc was confirmed in adrenal glands, as well as in mesenteric lymph nodes – a finding that was reported recently by another group. Interestingly, additional positive results were obtained for the first time in the oesophagus, abomasum, rumen and rectum of clinically affected cattle.

Prion protein gene sequence of Canada's first non-imported case of bovine spongiform encephalopathy (BSE)

Genome ◽  
2003 ◽  
Vol 46 (6) ◽  
pp. 1005-1009 ◽  
Author(s):  
Michael B Coulthart ◽  
Rhonda Mogk ◽  
Jason M Rancourt ◽  
Deborah L Godal ◽  
Stefanie Czub
Keyword(s):  
Bovine Spongiform Encephalopathy ◽  
Prion Protein ◽  
Protein Misfolding ◽  
Sequence Data ◽  
Spongiform Encephalopathy ◽  
Protein Coding ◽  
Dna Sequence Data ◽  
Imported Case ◽  
The United Kingdom ◽  
Jakob Disease

In May 2003, Canada became the 22nd country outside of the United Kingdom to report a case of bovine spongiform encephalopathy (BSE) in an animal not known to be imported from a country with cattle previously affected by this fatal, transmissible prion disease. Despite extensive testing of thousands of other animals that may have been exposed to contaminated feed at the same time as the affected animal, no evidence has been found for other infections. This finding leaves room for conjectures that the single confirmed case arose spontaneously, perhaps (by analogy with human Creutzfeldt–Jakob disease) as a result of a somatic protein misfolding event or a novel germline mutation. Here we present DNA sequence data from the affected animal's prion protein coding sequence that argue definitively against the latter hypothesis.Key words: bovine spongiform encephalopathy, spontaneous origin, prions, mutation, Canada.

scholarly journals Guinea Pig Prion Protein Supports Rapid Propagation of Bovine Spongiform Encephalopathy and Variant Creutzfeldt-Jakob Disease Prions

2016 ◽  
Vol 90 (21) ◽  
pp. 9558-9569 ◽  
Author(s):  
Joel C. Watts ◽  
Kurt Giles ◽  
Daniel J. Saltzberg ◽  
Brittany N. Dugger ◽  
Smita Patel ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Bovine Spongiform Encephalopathy ◽  
Prion Protein ◽  
Guinea Pigs ◽  
Spongiform Encephalopathy ◽  
Prolonged Incubation ◽  
Rapid Propagation ◽  
Incubation Periods ◽  
Jakob Disease ◽  
Sporadic Cjd

ABSTRACTThe biochemical and neuropathological properties of bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) prions are faithfully maintained upon transmission to guinea pigs. However, primary and secondary transmissions of BSE and vCJD in guinea pigs result in long incubation periods of ∼450 and ∼350 days, respectively. To determine if the incubation periods of BSE and vCJD prions could be shortened, we generated transgenic (Tg) mice expressing guinea pig prion protein (GPPrP). Inoculation of Tg(GPPrP) mice with BSE and vCJD prions resulted in mean incubation periods of 210 and 199 days, respectively, which shortened to 137 and 122 days upon serial transmission. In contrast, three different isolates of sporadic CJD prions failed to transmit disease to Tg(GPPrP) mice. Many of the strain-specified biochemical and neuropathological properties of BSE and vCJD prions, including the presence of type 2 protease-resistant PrPSc, were preserved upon propagation in Tg(GPPrP) mice. Structural modeling revealed that two residues near the N-terminal region of α-helix 1 in GPPrP might mediate its susceptibility to BSE and vCJD prions. Our results demonstrate that expression of GPPrP in Tg mice supports the rapid propagation of BSE and vCJD prions and suggest that Tg(GPPrP) mice may serve as a useful paradigm for bioassaying these prion isolates.IMPORTANCEVariant Creutzfeldt-Jakob disease (vCJD) and bovine spongiform encephalopathy (BSE) prions are two of the prion strains most relevant to human health. However, propagating these strains in mice expressing human or bovine prion protein has been difficult because of prolonged incubation periods or inefficient transmission. Here, we show that transgenic mice expressing guinea pig prion protein are fully susceptible to vCJD and BSE prions but not to sporadic CJD prions. Our results suggest that the guinea pig prion protein is a better, more rapid substrate than either bovine or human prion protein for propagating BSE and vCJD prions.

scholarly journals Prion Protein Alleles Showing a Protective Effect on the Susceptibility of Sheep to Scrapie and Bovine Spongiform Encephalopathy

2007 ◽  
Vol 81 (13) ◽  
pp. 7306-7309 ◽  
Author(s):  
Gabriele Vaccari ◽  
Claudia D'Agostino ◽  
Romolo Nonno ◽  
Francesca Rosone ◽  
Michela Conte ◽  
...  
Keyword(s):  
Amino Acid ◽  
Protective Effect ◽  
Bovine Spongiform Encephalopathy ◽  
Prion Protein ◽  
Amino Acid Substitution ◽  
Classical Scrapie ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathy ◽  
Spongiform Encephalopathies ◽  
Disease Eradication

ABSTRACT The susceptibility of sheep to classical scrapie and bovine spongiform encephalopathy (BSE) is mainly influenced by prion protein (PrP) polymorphisms A136V, R154H, and Q171R, with the ARR allele associated with significantly decreased susceptibility. Here we report the protective effect of the amino acid substitution M137T, I142K, or N176K on the ARQ allele in sheep experimentally challenged with either scrapie or BSE. Such observations suggest the existence of additional PrP alleles that significantly decrease the susceptibility of sheep to transmissible spongiform encephalopathies, which may have important implications for disease eradication strategies.

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