scholarly journals PrP(d) accumulation in organs of ARQ/ARQ sheep experimentally infected with BSE by peripheral routes.

2006 ◽  
Vol 53 (2) ◽  
pp. 399-405 ◽  
Author(s):  
Stéphane Lezmi ◽  
Frédéric Ronzon ◽  
Anna Bencsik ◽  
Alexandre Bedin ◽  
Didier Calavas ◽  
...  
Keyword(s):  
Prion Protein ◽  
Peripheral Nerves ◽  
Clinical Symptoms ◽  
Prion Diseases ◽  
Small Ruminants ◽  
Brain Homogenate ◽  
Spongiform Encephalopathy ◽  
Post Inoculation ◽  
Muscle Types ◽  
Immunohistochemical Methods

To study the pathogenesis of bovine spongiform encephalopathy infection in small ruminants, two Lacaune sheep with the AA136RR154QQ171 and one with the AA136RR154RR171 genotype for the prion protein, were inoculated with a brain homogenate from a French cattle BSE case by peripheral routes. Sheep with the ARQ/ARQ genotype are considered as susceptible to prion diseases contrary to those with the ARR/ARR genotype. The accumulation of disease-associated prion protein (PrP(d)) was analysed by biochemical and immunohistochemical methods. No PrP(d) accumulation was detected in samples from the ARR/ARR sheep 2 years post inoculation. In the two ARQ/ARQ sheep that had scrapie-like clinical symptoms, PrP(d) was found in the central, sympathetic and enteric nervous systems and in lymphoid organs. Remarkably, PrP(d) was also detected in some muscle types as well as in all peripheral nerves that had not been reported previously thus revealing a widespread distribution of BSE-associated PrP(d) in sheep tissues.

scholarly journals Classical and Atypical Scrapie in Sheep and Goats. Review on the Etiology, Genetic Factors, Pathogenesis, Diagnosis, and Control Measures of Both Diseases

Animals ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 691
Author(s):  
Cristina Acín ◽  
Rosa Bolea ◽  
Marta Monzón ◽  
Eva Monleón ◽  
Bernardino Moreno ◽  
...  
Keyword(s):  
Prion Protein ◽  
Genetic Factors ◽  
Prion Diseases ◽  
Transmissible Spongiform Encephalopathy ◽  
Fatal Outcome ◽  
Small Ruminants ◽  
Cellular Prion Protein ◽  
Spongiform Encephalopathy ◽  
Atypical Scrapie ◽  
Sheep And Goats

Prion diseases, such as scrapie, are neurodegenerative diseases with a fatal outcome, caused by a conformational change of the cellular prion protein (PrPC), originating with the pathogenic form (PrPSc). Classical scrapie in small ruminants is the paradigm of prion diseases, as it was the first transmissible spongiform encephalopathy (TSE) described and is the most studied. It is necessary to understand the etiological properties, the relevance of the transmission pathways, the infectivity of the tissues, and how we can improve the detection of the prion protein to encourage detection of the disease. The aim of this review is to perform an overview of classical and atypical scrapie disease in sheep and goats, detailing those special issues of the disease, such as genetic factors, diagnostic procedures, and surveillance approaches carried out in the European Union with the objective of controlling the dissemination of scrapie disease.

scholarly journals Detection of RNA in the Plasma of Patients with Sporadic Creutzfeldt–Jakob Disease, Gerstmann–Straüssler Syndrome and Other Non-Transmissible Spongiform Encephalopathy Brain Disorders

2010 ◽  
Vol 3 ◽  
pp. MBI.S4043
Author(s):  
Kazuo Tsukui ◽  
Yasushi Iwasaki ◽  
Masamitsu Nagaoka ◽  
Kenji Tadokoro
Keyword(s):  
Prion Protein ◽  
Prion Diseases ◽  
Transmissible Spongiform Encephalopathy ◽  
Infectious Agent ◽  
Brain Homogenate ◽  
Proteinase K ◽  
Spongiform Encephalopathy ◽  
Brain Disorders ◽  
Rna Molecules ◽  
Jakob Disease

The infectious agent of transmissible spongiform encephalopathy (TSE) was assumed to be the aggregate of abnormal prion protein isoform (PrPsc). We observed that lowering the pH of 3% SDS-inoculated plasma or brain homogenate after PK digestion to 4.5 (acidic SDS condition) enabled to precipitate proteinase K-resistant prion protein (PrPres) in plasma as well as PrPres in the brain with synthetic poly-A RNA as affinity aggregate. Therefore, we determined if RNA molecules could be used for discriminating TSE patients from healthy individuals. We also examined the plasma of patients with classical Creutzfeldt–Jakob disease (CJD) and other brain disorders who were not diagnosed with TSE. The results indicated that RNA approximately 1.5–2.0 kb in length was commonly observed in the plasma of patients with brain disorders but was not detected in the plasma of healthy volunteers. Enhanced expression of RNA and its protection from endogenous nucleases might occur in the former group of patients. Moreover, we speculate that the non-transmissible neuronal disorders overlap with prion diseases.

scholarly journals PrP P102L and Nearby Lysine Mutations Promote Spontaneous In Vitro Formation of Transmissible Prions

2017 ◽  
Vol 91 (21) ◽  
Author(s):  
Allison Kraus ◽  
Gregory J. Raymond ◽  
Brent Race ◽  
Katrina J. Campbell ◽  
Andrew G. Hughson ◽  
...  
Keyword(s):  
Prion Protein ◽  
Prion Diseases ◽  
Transmissible Spongiform Encephalopathy ◽  
Clinical Signs ◽  
Protein Aggregates ◽  
Structural Features ◽  
Spongiform Encephalopathy ◽  
Specific Sequence

ABSTRACT Accumulation of fibrillar protein aggregates is a hallmark of many diseases. While numerous proteins form fibrils by prion-like seeded polymerization in vitro, only some are transmissible and pathogenic in vivo. To probe the structural features that confer transmissibility to prion protein (PrP) fibrils, we have analyzed synthetic PrP amyloids with or without the human prion disease-associated P102L mutation. The formation of infectious prions from PrP molecules in vitro has required cofactors and/or unphysiological denaturing conditions. Here, we demonstrate that, under physiologically compatible conditions without cofactors, the P102L mutation in recombinant hamster PrP promoted prion formation when seeded by minute amounts of scrapie prions in vitro. Surprisingly, combination of the P102L mutation with charge-neutralizing substitutions of four nearby lysines promoted spontaneous prion formation. When inoculated into hamsters, both of these types of synthetic prions initiated substantial accumulation of prion seeding activity and protease-resistant PrP without transmissible spongiform encephalopathy (TSE) clinical signs or notable glial activation. Our evidence suggests that PrP's centrally located proline and lysine residues act as conformational switches in the in vitro formation of transmissible PrP amyloids. IMPORTANCE Many diseases involve the damaging accumulation of specific misfolded proteins in thread-like aggregates. These threads (fibrils) are capable of growing on the ends by seeding the refolding and incorporation of the normal form of the given protein. In many cases such aggregates can be infectious and propagate like prions when transmitted from one individual host to another. Some transmitted aggregates can cause fatal disease, as with human iatrogenic prion diseases, while other aggregates appear to be relatively innocuous. The factors that distinguish infectious and pathogenic protein aggregates from more innocuous ones are poorly understood. Here we have compared the combined effects of prion seeding and mutations of prion protein (PrP) on the structure and transmission properties of synthetic PrP aggregates. Our results highlight the influence of specific sequence features in the normally unstructured region of PrP that influence the infectious and neuropathogenic properties of PrP-derived aggregates.

scholarly journals Assessment of the PrP c Amino-Terminal Domain in Prion Species Barriers

2016 ◽  
Vol 90 (23) ◽  
pp. 10752-10761 ◽  
Author(s):  
Kristen A. Davenport ◽  
Davin M. Henderson ◽  
Candace K. Mathiason ◽  
Edward A. Hoover
Keyword(s):  
Prion Protein ◽  
Bank Vole ◽  
Protein Misfolding ◽  
Prion Diseases ◽  
Full Length ◽  
Spongiform Encephalopathy ◽  
Amino Terminal ◽  
Terminal Domain ◽  
Human Sequence ◽  
Amino Terminal Domain

ABSTRACT Chronic wasting disease (CWD) in cervids and bovine spongiform encephalopathy (BSE) in cattle are prion diseases that are caused by the same protein-misfolding mechanism, but they appear to pose different risks to humans. We are interested in understanding the differences between the species barriers of CWD and BSE. We used real-time, quaking-induced conversion (RT-QuIC) to model the central molecular event in prion disease, the templated misfolding of the normal prion protein, PrP c , to a pathogenic, amyloid isoform, scrapie prion protein, PrP Sc . We examined the role of the PrP c amino-terminal domain (N-terminal domain [NTD], amino acids [aa] 23 to 90) in cross-species conversion by comparing the conversion efficiency of various prion seeds in either full-length (aa 23 to 231) or truncated (aa 90 to 231) PrP c . We demonstrate that the presence of white-tailed deer and bovine NTDs hindered seeded conversion of PrP c , but human and bank vole NTDs did the opposite. Additionally, full-length human and bank vole PrP c s were more likely to be converted to amyloid by CWD prions than were their truncated forms. A chimera with replacement of the human NTD by the bovine NTD resembled human PrP c . The requirement for an NTD, but not for the specific human sequence, suggests that the NTD interacts with other regions of the human PrP c to increase promiscuity. These data contribute to the evidence that, in addition to primary sequence, prion species barriers are controlled by interactions of the substrate NTD with the rest of the substrate PrP c molecule. IMPORTANCE We demonstrate that the amino-terminal domain of the normal prion protein, PrP c , hinders seeded conversion of bovine and white-tailed deer PrP c s to the prion forms, but it facilitates conversion of the human and bank vole PrP c s to the prion forms. Additionally, we demonstrate that the amino-terminal domain of human and bank vole PrP c s requires interaction with the rest of the molecule to facilitate conversion by CWD prions. These data suggest that interactions of the amino-terminal domain with the rest of the PrP c molecule play an important role in the susceptibility of humans to CWD prions.

scholarly journals N-Terminal Regions of Prion Protein: Functions and Roles in Prion Diseases

2020 ◽  
Vol 21 (17) ◽  
pp. 6233
Author(s):  
Hideyuki Hara ◽  
Suehiro Sakaguchi
Keyword(s):  
Prion Protein ◽  
Structural Changes ◽  
Prion Diseases ◽  
Normal Function ◽  
Terminal Region ◽  
Spongiform Encephalopathy ◽  
Charged Residue ◽  
Terminal Domain ◽  
Polybasic Region ◽  
Positively Charged

The normal cellular isoform of prion protein, designated PrPC, is constitutively converted to the abnormally folded, amyloidogenic isoform, PrPSc, in prion diseases, which include Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy in animals. PrPC is a membrane glycoprotein consisting of the non-structural N-terminal domain and the globular C-terminal domain. During conversion of PrPC to PrPSc, its 2/3 C-terminal region undergoes marked structural changes, forming a protease-resistant structure. In contrast, the N-terminal region remains protease-sensitive in PrPSc. Reverse genetic studies using reconstituted PrPC-knockout mice with various mutant PrP molecules have revealed that the N-terminal domain has an important role in the normal function of PrPC and the conversion of PrPC to PrPSc. The N-terminal domain includes various characteristic regions, such as the positively charged residue-rich polybasic region, the octapeptide repeat (OR) region consisting of five repeats of an octapeptide sequence, and the post-OR region with another positively charged residue-rich polybasic region followed by a stretch of hydrophobic residues. We discuss the normal functions of PrPC, the conversion of PrPC to PrPSc, and the neurotoxicity of PrPSc by focusing on the roles of the N-terminal regions in these topics.

Comparison of Brain PrPd Distribution in Ovine BSE and Scrapie

2011 ◽  
Vol 48 (6) ◽  
pp. 1101-1108 ◽  
Author(s):  
S. Lezmi ◽  
T. Seuberlich ◽  
A. Oevermann ◽  
T. Baron ◽  
A. Bencsik
Keyword(s):  
Frontal Cortex ◽  
Prion Diseases ◽  
Piriform Cortex ◽  
Small Ruminants ◽  
Infected Sheep ◽  
Spongiform Encephalopathy ◽  
Genotype Distribution ◽  
Prion Strains ◽  
Incubation Periods ◽  
The Brain

Scrapie and bovine spongiform encephalopathy (BSE) are both prion diseases affecting ruminants, and these diseases do not share the same public health concerns. Surveillance of the BSE agent in small ruminants has been a great challenge, and the recent identification of diverse prion diseases in ruminants has led to the development of new methods for strain typing. In our study, using immunohistochemistry (IHC), we assessed the distribution of PrPd in the brains of 2 experimentally BSE-infected sheep with the ARQ/ARQ genotype. Distribution of PrPd in the brain, from the spinal cord to the frontal cortex, was remarkably similar in the 2 sheep despite different inoculation routes and incubation periods. Comparatively, overall PrPd brain distribution, evaluated by IHC, in 19 scrapie cases with the ARQ/ARQ, ARQ/VRQ, and VRQ/VRQ genotypes, in some cases showed similarities to the experimentally BSE-infected sheep. There was no exclusive neuroanatomical site with a characteristic and specific PrPd type of accumulation induced by the BSE agent. However, a detailed analysis of the topography, types, and intensity of PrPd deposits in the frontal cortex, striatum, piriform cortex, hippocampus, mesencephalon, and cerebellum allowed the BSE-affected sheep group to be distinguished from the 19 scrapie cases analyzed in our study. These results strengthen and emphasize the potential interest of PrPd brain mapping to help in identifying prion strains in small ruminants.

scholarly journals Detection and Discrimination of Classical and Atypical L-Type Bovine Spongiform Encephalopathy by Real-Time Quaking-Induced Conversion

2015 ◽  
Vol 53 (4) ◽  
pp. 1115-1120 ◽  
Author(s):  
Christina D. Orrú ◽  
Alessandra Favole ◽  
Cristiano Corona ◽  
Maria Mazza ◽  
Matteo Manca ◽  
...  
Keyword(s):  
Bovine Spongiform Encephalopathy ◽  
Real Time ◽  
Brain Tissue ◽  
Prion Protein ◽  
Rapid Detection ◽  
Prion Diseases ◽  
Spongiform Encephalopathy ◽  
Diagnostic Strategy ◽  
The Real ◽  
Recombinant Prion Protein

Statutory surveillance of bovine spongiform encephalopathy (BSE) indicates that cattle are susceptible to both classical BSE (C-BSE) and atypical forms of BSE. Atypical forms of BSE appear to be sporadic and thus may never be eradicated. A major challenge for prion surveillance is the lack of sufficiently practical and sensitive tests for routine BSE detection and strain discrimination. The real-time quaking-induced conversion (RT-QuIC) test, which is based on prion-seeded fibrillization of recombinant prion protein (rPrPSen), is known to be highly specific and sensitive for the detection of multiple human and animal prion diseases but not BSE. Here, we tested brain tissue from cattle affected by C-BSE and atypical L-type bovine spongiform encephalopathy (L-type BSE or L-BSE) with the RT-QuIC assay and found that both BSE forms can be detected and distinguished using particular rPrPSensubstrates. Specifically, L-BSE was detected using multiple rPrPSensubstrates, while C-BSE was much more selective. This substrate-based approach suggests a diagnostic strategy for specific, sensitive, and rapid detection and discrimination of at least some BSE forms.

scholarly journals Prionic diseases

2013 ◽  
Vol 71 (9B) ◽  
pp. 731-737 ◽  
Author(s):  
Abelardo Q-C Araujo
Keyword(s):  
Prion Protein ◽  
Clinical Symptoms ◽  
Prion Diseases ◽  
Brain Biopsy ◽  
Gene Encoding ◽  
Genetic Studies ◽  
Familial Predisposition ◽  
Jakob Disease ◽  
In Vivo Diagnosis

Prion diseases are neurodegenerative illnesses due to the accumulation of small infectious pathogens containing protein but apparently lacking nucleic acid, which have long incubation periods and progress inexorably once clinical symptoms appear. Prions are uniquely resistant to a number of normal decontaminating procedures. The prionopathies [Kuru, Creutzfeldt-Jakob disease (CJD) and its variants, Gerstmann-Sträussler-Scheinker (GSS) syndrome and fatal familial insomnia (FFI)] result from accumulation of abnormal isoforms of the prion protein in the brains of normal animals on both neuronal and non-neuronal cells. The accumulation of this protein or fragments of it in neurons leads to apoptosis and cell death. There is a strong link between mutations in the gene encoding the normal prion protein in humans (PRNP) - located on the short arm of chromosome 20 – and forms of prion disease with a familial predisposition (familial CJD, GSS, FFI). Clinically a prionopathy should be suspected in any case of a fast progressing dementia with ataxia, myoclonus, or in individuals with pathological insomnia associated with dysautonomia. Magnetic resonance imaging, identification of the 14-3-3 protein in the cerebrospinal fluid, tonsil biopsy and genetic studies have been used for in vivo diagnosis circumventing the need of brain biopsy. Histopathology, however, remains the only conclusive method to reach a confident diagnosis. Unfortunately, despite numerous treatment efforts, prionopathies remain short-lasting and fatal diseases.

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 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.

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