Role of the PrP Gene in Transmissible Spongiform Encephalopathies

Intervirology ◽  
1993 ◽  
Vol 35 (1-4) ◽  
pp. 164-175 ◽  
Author(s):  
Charles Weissmann ◽  
Hansruedi Büeler ◽  
Marek Fischer ◽  
Michel Aguet
Keyword(s):  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathies ◽  
Prp Gene

scholarly journals Expression of doppel in the CNS of mice does not modulate transmissible spongiform encephalopathy disease

2002 ◽  
Vol 83 (3) ◽  
pp. 705-711 ◽  
Author(s):  
Nadia L. Tuzi ◽  
Elaine Gall ◽  
David Melton ◽  
Jean C. Manson
Keyword(s):  
Late Onset ◽  
Transmissible Spongiform Encephalopathy ◽  
Structural Similarity ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathy ◽  
Spongiform Encephalopathies ◽  
Naturally Occurring ◽  
Prp Gene ◽  
Apparent Influence

Late onset ataxia reported in three independently derived PrP null lines of mice has been attributed to the overexpression of the doppel protein in the CNS of these mice rather than to the loss of PrP. The central role of PrP in the transmissible spongiform encephalopathies (TSEs), the proximity of the gene which encodes doppel (Prnd) to the PrP gene (Prnp) and the structural similarity shared by PrP and doppel have led to the proposition that ataxia which develops during TSE disease could, in part, be due to doppel. In order to address this hypothesis, we have crossed our two inbred lines of PrP null mice, which either express (RCM) or do not express (NPU) the Prnd gene in the CNS, with mice expressing two Prnp a[108F189V] alleles of the PrP gene. We have found that the TSE infection does not influence the level of expression of Prnd in the CNS at the terminal stages of disease. Moreover, we have demonstrated that the level of expression of Prnd in the CNS has no influence on the incubation period, vacuolar pathology nor amount or distribution of PrPSc deposition in the brains of the TSE-infected mice. Doppel has therefore no apparent influence on the outcome of TSE disease in transgenic mice, suggesting it is unlikely to be involved in the naturally occurring TSE diseases in other species.

Prions: Protein Aggregation and Infectious Diseases

2009 ◽  
Vol 89 (4) ◽  
pp. 1105-1152 ◽  
Author(s):  
Adriano Aguzzi ◽  
Anna Maria Calella
Keyword(s):  
Protein Aggregation ◽  
Prion Diseases ◽  
Physiological Role ◽  
Infectious Agent ◽  
Normal Function ◽  
Cellular Prion Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Pathological Features ◽  
Spongiform Encephalopathies

Transmissible spongiform encephalopathies (TSEs) are inevitably lethal neurodegenerative diseases that affect humans and a large variety of animals. The infectious agent responsible for TSEs is the prion, an abnormally folded and aggregated protein that propagates itself by imposing its conformation onto the cellular prion protein (PrPC) of the host. PrPCis necessary for prion replication and for prion-induced neurodegeneration, yet the proximal causes of neuronal injury and death are still poorly understood. Prion toxicity may arise from the interference with the normal function of PrPC, and therefore, understanding the physiological role of PrPCmay help to clarify the mechanism underlying prion diseases. Here we discuss the evolution of the prion concept and how prion-like mechanisms may apply to other protein aggregation diseases. We describe the clinical and the pathological features of the prion diseases in human and animals, the events occurring during neuroinvasion, and the possible scenarios underlying brain damage. Finally, we discuss potential antiprion therapies and current developments in the realm of prion diagnostics.

scholarly journals Strictly co-isogenic C57BL/6J-Prnp−/− mice: A rigorous resource for prion science

2016 ◽  
Vol 213 (3) ◽  
pp. 313-327 ◽  
Author(s):  
Mario Nuvolone ◽  
Mario Hermann ◽  
Silvia Sorce ◽  
Giancarlo Russo ◽  
Cinzia Tiberi ◽  
...  
Keyword(s):  
Laboratory Mouse ◽  
Embryonic Stem ◽  
Physiological Role ◽  
Cellular Prion Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Phenotypic Characterization ◽  
Spongiform Encephalopathies ◽  
Demyelinating Peripheral Neuropathy

Although its involvement in prion replication and neurotoxicity during transmissible spongiform encephalopathies is undisputed, the physiological role of the cellular prion protein (PrPC) remains enigmatic. A plethora of functions have been ascribed to PrPC based on phenotypes of Prnp−/− mice. However, all currently available Prnp−/− lines were generated in embryonic stem cells from the 129 strain of the laboratory mouse and mostly crossed to non-129 strains. Therefore, Prnp-linked loci polymorphic between 129 and the backcrossing strain resulted in systematic genetic confounders and led to erroneous conclusions. We used TALEN-mediated genome editing in fertilized mouse oocytes to create the Zurich-3 (ZH3) Prnp-ablated allele on a pure C57BL/6J genetic background. Genomic, transcriptional, and phenotypic characterization of PrnpZH3/ZH3 mice failed to identify phenotypes previously described in non–co-isogenic Prnp−/− mice. However, aged PrnpZH3/ZH3 mice developed a chronic demyelinating peripheral neuropathy, confirming the crucial involvement of PrPC in peripheral myelin maintenance. This new line represents a rigorous genetic resource for studying the role of PrPC in physiology and disease.

scholarly journals Scrapie Resistance Gene Identification using Optimized Taqman Test qPCR Method in Sheep on the Territory of the Republic of Serbia

2021 ◽  
Vol 71 (2) ◽  
pp. 189-197
Author(s):  
Slađan Nešić ◽  
Stefan Jelisić ◽  
Sanja Aleksić-Kovačević ◽  
Milan Aničić ◽  
Ivana Vučićević
Keyword(s):  
Gene Identification ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathies ◽  
Resistant Genotype ◽  
Taqman Probes ◽  
Qpcr Method ◽  
The Central Nervous System ◽  
Polymerase Chain ◽  
The Republic ◽  
Prp Gene

Abstract Scrapie is an infectious neurodegenerative disease affecting the central nervous system of sheep and goats that belongs to transmissible spongiform encephalopathies. The disease is caused by the accumulation of proteinase-resistant isoform of the prion protein. The sheep predisposition to scrapie is associated with polymorphisms of the PrP gene. Genetic susceptibility to scrapie is mainly related to codons 136, 154, and 171. ARR sheep are strongly scrapie resistant and VRQ genotype is the most susceptible. Many countries have scrapie eradication programs based on using rams with resistant genotype. The eradication program has not yet been implemented in the Republic of Serbia. To examine the genetic makeup of sheep in Serbia related to scrapie, we optimized TaqMan probes of real-time polymerase chain reaction (qPCR) technique for three codons. Blood samples from 100 sheep were analyzed by qPCR and the majority of the examined sheep were AA homozygous for the 136 codon. For codon 154 the most frequent genotype was RR and for codon 171 the most frequent genotype was QQ.

scholarly journals Structural Consequences of Copper Binding to the Prion Protein

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 770 ◽  
Author(s):  
Giulia Salzano ◽  
Gabriele Giachin ◽  
Giuseppe Legname
Keyword(s):  
Prion Protein ◽  
Animal Species ◽  
State Of The Art ◽  
Copper Ions ◽  
Cellular Prion Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Copper Binding ◽  
Spongiform Encephalopathies ◽  
And Function

Prion, or PrPSc, is the pathological isoform of the cellular prion protein (PrPC) and it is the etiological agent of transmissible spongiform encephalopathies (TSE) affecting humans and animal species. The most relevant function of PrPC is its ability to bind copper ions through its flexible N-terminal moiety. This review includes an overview of the structure and function of PrPC with a focus on its ability to bind copper ions. The state-of-the-art of the role of copper in both PrPC physiology and in prion pathogenesis is also discussed. Finally, we describe the structural consequences of copper binding to the PrPC structure.

scholarly journals Creutzfeldt-Jakob disease: a review of current available evidence and the implications for prehospital emergency care.

2016 ◽  
Vol 13 (3) ◽  
Author(s):  
Hannah Adele Kirby
Keyword(s):  
Transmissible Spongiform Encephalopathies ◽  
Prehospital Emergency Care ◽  
Training And Education ◽  
Spongiform Encephalopathies ◽  
Cochrane Database ◽  
Jakob Disease ◽  
Prehospital Emergency ◽  
Management Techniques ◽  
Spread Of Infection

Introduction: Creutzfeldt-Jakob Disease effects 1 in 1 million people globally per year. It is an invariable fatal neurodegenerative disease belonging to the group of transmissible spongiform encephalopathies.  This review aims to examine the current clinical evidence surrounding CJD, as well as present management techniques to assist in minimizing the effect of symptoms. This review also highlights the important role of paramedics in reducing mortality and morbidity.Methods: An electronic search was conducted using Medline (Via EBSCOHost), CINAHL, and the Cochrane Database of Systematic Reviews. Results: This search resulted in 265 articles. Articles unavailable as full text, those not available in English, those articles not peer reviewed, and review articles were all excluded from analysis. The remaining 16 articles met the search criteria and were included in this report.Conclusion: Scientific advancements are bringing a cure closer to reality, however further scientific research needs to be conducted. Training and education programs should be made available to prehospital workers to prevent further spread of infection.

scholarly journals INTERRELATION OF PRIONS WITH NON-CODING RNAS

2018 ◽  
Vol 22 (4) ◽  
pp. 415-424
Author(s):  
R. N. Mustafin ◽  
E. K. Khusnutdinova
Keyword(s):  
Prion Diseases ◽  
Noncoding Rnas ◽  
Transmissible Spongiform Encephalopathies ◽  
Regulatory Effect ◽  
Spongiform Encephalopathies ◽  
Neuronal Stem Cells ◽  
Non Coding Rnas ◽  
The Brain ◽  
Brain Tissues

Prions are alternative infectious conformations for some cellular proteins. For the protein PrPC(PrP – prion protein, С – common), a prion conformation, called PrPSc(S – scrapie), is pathological. For example, in mammals the PrPScprion causes transmissible spongiform encephalopathies accumulating in the brain tissues of PrPScaggregates that have amyloid properties. MicroRNAs and long non-coding RNAs can be translated into functional peptides. These peptides can have a regulatory effect on genes from which their non-coding RNAs are transcribed. It has been assumed that prions, like peptides, due to the presence of specific domains, can also activate certain non-coding RNAs. Some of the activated non-coding RNAs can catalyze the formation of new prions from normal protein, playing their role in the pathogenesis of prion diseases. Confirmation of this assumption is the presence of the association of alleles of microRNA with the development of the disease, which indicates the role of the specific sequences of noncoding RNAs in the catalysis of prion formation. In the brain tissues of patients with prion diseases, as well as in exosomes containing an abnormal PrPScisoform, changes in the levels of microRNA have been observed. A possible cause is the interaction of the spatial domains of PrPScwith the sequences of the non-coding RNA genes, which causes a change in their expression. MicroRNAs, in turn, affect the synthesis of long non-coding RNAs. We hypothesize that long noncoding RNAs and possibly microRNAs can interact with PrPCcatalyzing its transformation into PrPSc. As a result, the number of PrPScincreases exponentially. In the brain of animals and humans, transposon activity has been observed, which has a regulatory effect on the differentiation of neuronal stem cells. Transposons form the basis of domain structures of long non-coding RNAs. In addition, they are important sources of microRNA. Since prion diseases can arise as sporadic and hereditary cases, and hereditary predisposition is important for the development of pathology, we hypothesize the role of individual features of activation of transposons in the pathogenesis of prion diseases. The activation of transposons in the brain at certain stages of development, as well as under the influence of stress, is reflected in the peculiarities of expression of specific non-coding RNAs that are capable of catalyzing the transition of the PrPCprotein to PrPSc. Research in this direction can be the basis for targeted anti-microRNA therapy of prion diseases.

scholarly journals Quercetin Disaggregates Prion Fibrils and Decreases Fibril-Induced Cytotoxicity and Oxidative Stress

Pharmaceutics ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1081
Author(s):  
Kun-Hua Yu ◽  
Cheng-I Lee
Keyword(s):  
Oxidative Stress ◽  
Prion Protein ◽  
Amyloid Fibrils ◽  
Neuroblastoma Cells ◽  
Amyloid Β ◽  
Transmissible Spongiform Encephalopathies ◽  
Amyloid Β Peptide ◽  
Hemolysis Assay ◽  
Spongiform Encephalopathies

Transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative diseases caused by misfolding and aggregation of prion protein (PrP). Previous studies have demonstrated that quercetin can disaggregate some amyloid fibrils, such as amyloid β peptide (Aβ) and α-synuclein. However, the disaggregating ability is unclear in PrP fibrils. In this study, we examined the amyloid fibril-disaggregating activity of quercetin on mouse prion protein (moPrP) and characterized quercetin-bound moPrP fibrils by imaging, proteinase resistance, hemolysis assay, cell viability, and cellular oxidative stress measurements. The results showed that quercetin treatment can disaggregate moPrP fibrils and lead to the formation of the proteinase-sensitive amorphous aggregates. Furthermore, quercetin-bound fibrils can reduce the membrane disruption of erythrocytes. Consequently, quercetin-bound fibrils cause less oxidative stress, and are less cytotoxic to neuroblastoma cells. The role of quercetin is distinct from the typical function of antiamyloidogenic drugs that inhibit the formation of amyloid fibrils. This study provides a solution for the development of antiamyloidogenic therapy.

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