scholarly journals Human Prion Disorders: Review of the Current Literature and a Twenty-Year Experience of the National Surveillance Center in the Czech Republic

Diagnostics ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1821
Author(s):  
Nikol Jankovska ◽  
Robert Rusina ◽  
Magdalena Bruzova ◽  
Eva Parobkova ◽  
Tomas Olejar ◽  
...  
Keyword(s):  
Czech Republic ◽  
Prion Protein ◽  
Active Surveillance ◽  
Current Knowledge ◽  
Prion Diseases ◽  
Transmissible Spongiform Encephalopathies ◽  
National Surveillance ◽  
Spongiform Encephalopathies ◽  
Tissue Samples ◽  
The Czech Republic

Human prion disorders (transmissible spongiform encephalopathies, TSEs) are unique, progressive, and fatal neurodegenerative diseases caused by aggregation of misfolded prion protein in neuronal tissue. Due to the potential transmission, human TSEs are under active surveillance in a majority of countries; in the Czech Republic data are centralized at the National surveillance center (NRL) which has a clinical and a neuropathological subdivision. The aim of our article is to review current knowledge about human TSEs and summarize the experience of active surveillance of human prion diseases in the Czech Republic during the last 20 years. Possible or probable TSEs undergo a mandatory autopsy using a standardized protocol. From 2001 to 2020, 305 cases of sporadic and genetic TSEs including 8 rare cases of Gerstmann–Sträussler–Scheinker syndrome (GSS) were confirmed. Additionally, in the Czech Republic, brain samples from all corneal donors have been tested by the NRL immunology laboratory to increase the safety of corneal transplants since January 2007. All tested 6590 corneal donor brain tissue samples were negative for prion protein deposits. Moreover, the routine use of diagnostic criteria including biomarkers are robust enough, and not even the COVID-19 pandemic has negatively impacted TSEs surveillance in the Czech Republic.

scholarly journals Generation of Antibodies against Bovine Recombinant Prion Protein in Various Strains of Mice

2006 ◽  
Vol 13 (1) ◽  
pp. 98-105 ◽  
Author(s):  
Olga Andrievskaia ◽  
Heather McRae ◽  
Cathy Elmgren ◽  
Hongsheng Huang ◽  
Aru Balachandran ◽  
...  
Keyword(s):  
Prion Protein ◽  
Prion Diseases ◽  
Basic Research ◽  
Transmissible Spongiform Encephalopathies ◽  
Enzyme Linked Immunosorbent Assay ◽  
Spongiform Encephalopathies ◽  
Tissue Samples ◽  
Antibody Titers ◽  
Sheep Brain ◽  
Recombinant Prion Protein

ABSTRACT Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, belong to a group of neurodegenerative disorders affecting humans and animals. To date, definite diagnosis of prion disease can only be made by analysis of tissue samples for the presence of protease-resistant misfolded prion protein (PrPSc). Monoclonal antibodies (MAbs) to the prion protein provide valuable tools for TSE diagnosis, as well as for basic research on these diseases. In this communication, the development of antibodies against recombinant bovine prion protein (brecPrP) in four strains of mice (BALB/c, ND4, SJL, and NZB/NZW F1) is described. Immunization of autoimmunity-prone NZB/NZW F1 and SJL mice with brecPrP was applied to overcome self-tolerance against the prion protein. ND4 and SJL mice did not develop an immune response to brecPrP. BALB/c mice produced antibody titers of 1:1,000 to 1:1,500 in an enzyme-linked immunosorbent assay (ELISA), while NZB/NZW F1 mice responded with titers of 1:7,000 to 1:11,000. A panel of 71 anti-brecPrP MAbs recognizing continuous and discontinuous epitopes was established from BALB/c and NZB/NZW F1 mice. Seven anti-brecPrP MAbs reacted with both the cellular form of PrP and protease K-resistant PrPSc from sheep brain in Western blot assays. The epitope specificity of these MAbs was determined, and applicability to immunohistochemical detection of prions was studied. The MAbs generated will be useful tools in the development of TSE immunochemical diagnosis and for research. This is the first report of the development of anti-PrP MAbs by use of autoimmune NZB/NZW F1 mice as an alternative approach for the generation of PrP-specific MAbs.

scholarly journals Backbone NMR assignments of the C-terminal domain of the human prion protein and its disease‐associated T183A variant

2021 ◽  
Vol 15 (1) ◽  
pp. 193-196
Author(s):  
Máximo Sanz-Hernández ◽  
Alfonso De Simone
Keyword(s):  
Prion Protein ◽  
Nmr Assignments ◽  
Chemical Shifts ◽  
Prion Diseases ◽  
Random Coil ◽  
Transmissible Spongiform Encephalopathies ◽  
Globular Domain ◽  
Structural Elements ◽  
Spongiform Encephalopathies ◽  
Human Prion Protein

AbstractTransmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative disorders associated with the misfolding and aggregation of the human prion protein (huPrP). Despite efforts into investigating the process of huPrP aggregation, the mechanisms triggering its misfolding remain elusive. A number of TSE-associated mutations of huPrP have been identified, but their role at the onset and progression of prion diseases is unclear. Here we report the NMR assignments of the C-terminal globular domain of the wild type huPrP and the pathological mutant T183A. The differences in chemical shifts between the two variants reveal conformational alterations in some structural elements of the mutant, whereas the analyses of secondary shifts and random coil index provide indications on the putative mechanisms of misfolding of T183A huPrP.

Prion disease

2018 ◽  
Author(s):  
Richard Knight
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Prion Diseases ◽  
Human Diseases ◽  
Brain Diseases ◽  
Transmissible Spongiform Encephalopathies ◽  
Structural Form ◽  
Spongiform Encephalopathies ◽  
Spongiform Change ◽  
Neurodegenerative Pathology

Prion diseases (also known as transmissible spongiform encephalopathies (TSEs)) affect animals and humans, although only the human diseases will be discussed in this chapter. Despite TSEs having somewhat disparate causes and effects, there are unifying features: TSEs are brain diseases with neurodegenerative pathology, which is typically associated with spongiform change, and, most characteristically, there is tissue deposition of an abnormal structural form of the prion protein. Some of the TSEs are naturally acquired infections and, while others are not, they are potentially transmissible in certain circumstances.

Trace elements and prion diseases: a review of the interactions of copper, manganese and zinc with the prion protein

2006 ◽  
Vol 7 (1-2) ◽  
pp. 97-105 ◽  
Author(s):  
Scott P. Leach ◽  
M. D. Salman ◽  
Dwayne Hamar
Keyword(s):  
Trace Elements ◽  
Prion Protein ◽  
Copper Ions ◽  
Prion Diseases ◽  
Normal Function ◽  
Transmissible Spongiform Encephalopathies ◽  
Copper Binding ◽  
Spongiform Encephalopathies ◽  
Copper Manganese ◽  
The Brain

Transmissible spongiform encephalopathies (TSEs) are a family of neurodegenerative diseases characterized by their long incubation periods, progressive neurological changes, and spongiform appearance in the brain. There is much evidence to show that TSEs are caused by an isoform of the normal cellular surface prion protein PrPC. The normal function of PrPC is still unknown, but it exhibits properties of a cupro-protein, capable of binding up to six copper ions. There are two differing views on copper's role in prion diseases. While one view looks at the PrPC copper-binding as the trigger for conversion to PrPSc, the opposing viewpoint sees a lack of PrPC copper-binding resulting in the conformational change into the disease causing isoform. Manganese and zinc have been shown to interact with PrPC as well and have been found in abnormal levels in prion diseases. This review addresses the interaction between select trace elements and the PrPC.

Copper and prion diseases

2002 ◽  
Vol 30 (4) ◽  
pp. 742-745 ◽  
Author(s):  
D. R. Brown
Keyword(s):  
Prion Protein ◽  
Strong Evidence ◽  
Prion Diseases ◽  
Transmissible Spongiform Encephalopathies ◽  
Normal Brain ◽  
Spongiform Encephalopathies ◽  
Metal Metabolism ◽  
Jakob Disease ◽  
Anti Oxidant ◽  
Experimental Mouse

Transmissible spongiform encephalopathies are diseases of animals and humans that are also termed prion diseases. These diseases are linked together because a normal brain glycoprotein termed the prion protein is converted to a readily detectable protease-resistant isoform. There is now strong evidence to suggest that apart from this difference in resistance a major difference between the isoforms is that the normal prion protein binds copper and has an anti-oxidant function. Brains from Creutzfeldt-Jakob disease patients and brains from mice with experimental mouse scrapie have been shown to have changes in the levels of both copper and manganese. There is growing evidence that links prion diseases to disturbances of metal metabolism.

scholarly journals Prion protein interconversions†

2001 ◽  
Vol 356 (1406) ◽  
pp. 197-202 ◽  
Author(s):  
Byron Caughey
Keyword(s):  
Neurodegenerative Diseases ◽  
Prion Protein ◽  
Prion Diseases ◽  
Transmissible Spongiform Encephalopathies ◽  
Biological Parameters ◽  
Spongiform Encephalopathies ◽  
Lead Compounds ◽  
Resistant Form

The transmissible spongiform encephalopathies (TSEs), or prion diseases, remain mysterious neurodegenerative diseases that involve perturbations in prion protein (PrP) structure. This article summarizes our use of in vitro models to describe how PrP is converted to the disease–associated, protease–resistant form. These models reflect many important biological parameters of TSE diseases and have been used to identify inhibitors of the PrP conversion as lead compounds in the development of anti–TSE drugs.

scholarly journals Prion protein polymorphisms in white-tailed deer influence susceptibility to chronic wasting disease

2006 ◽  
Vol 87 (7) ◽  
pp. 2109-2114 ◽  
Author(s):  
Chad Johnson ◽  
Jody Johnson ◽  
Joshua P. Vanderloo ◽  
Delwyn Keane ◽  
Judd M. Aiken ◽  
...  
Keyword(s):  
Prion Protein ◽  
Chronic Wasting Disease ◽  
Prion Diseases ◽  
Transmissible Spongiform Encephalopathies ◽  
Genetic Barrier ◽  
Wasting Disease ◽  
Spongiform Encephalopathies ◽  
Population Comparison ◽  
Free Ranging ◽  
The Impact

The primary sequence of the prion protein affects susceptibility to transmissible spongiform encephalopathies, or prion diseases, in mice, sheep and humans. The Prnp gene sequence of free-ranging, Wisconsin white-tailed deer was determined and the Prnp genotypes of chronic wasting disease (CWD)-positive and CWD-negative deer were compared. Six amino acid changes were identified, two of which were located in pseudogenes. Two alleles, a Q→K polymorphism at codon 226 and a single octapeptide repeat insertion into the pseudogene, have not been reported previously. The predominant alleles – wild-type (Q95, G96 and Q226) and a G96S polymorphism – comprised almost 98 % of the Prnp alleles in the Wisconsin white-tailed deer population. Comparison of the allelic frequencies in the CWD-positive and CWD-negative deer suggested that G96S and a Q95H polymorphism were linked to a reduced susceptibility to CWD. The G96S allele did not, however, provide complete resistance, as a CWD-positive G96S/G96S deer was identified. The G96S allele was also linked to slower progression of the disease in CWD-positive deer based on the deposition of PrPCWD in the obex region of the medulla oblongata. Although the reduced susceptibility of deer with at least one copy of the Q95H or G96S allele is insufficient to serve as a genetic barrier, the presence of these alleles may modulate the impact of CWD on white-tailed deer populations.

scholarly journals Toxicological Evaluation of Anti-Scrapie Trimethoxychalcones and Oxadiazoles

2015 ◽  
Vol 87 (2 suppl) ◽  
pp. 1421-1434 ◽  
Author(s):  
CLAUDIA P. FIGUEIREDO ◽  
NATALIA C. FERREIRA ◽  
GISELLE F. PASSOS ◽  
ROBSON DA COSTA ◽  
FERNANDA S. NEVES ◽  
...  
Keyword(s):  
Prion Protein ◽  
Aromatic Compounds ◽  
Prion Diseases ◽  
Intraperitoneal Administration ◽  
Neuroblastoma Cells ◽  
Cellular Prion Protein ◽  
Transmissible Spongiform Encephalopathies ◽  
Toxicological Evaluation ◽  
Spongiform Encephalopathies

An altered form of the cellular prion protein, the PrPScor PrPRes, is implicated in the occurrence of the still untreatable transmissible spongiform encephalopathies. We have previously synthesized and characterized aromatic compounds that inhibit protease-resistant prion protein (PrPRes) accumulation in scrapie-infected cells. These compounds belong to different chemical classes, including acylhydrazones, chalcones and oxadiazoles. Some of the active compounds were non-toxic to neuroblastoma cells in culture and seem to possess drugable properties, since they are in agreement with the Lipinski´s rule of 5 and present desirable pharmacokinetic profiles as predicted in silico. Before the evaluation of the in vivo efficacy of the aromatic compounds in scrapie-infected mice, safety assessment in healthy mice is needed. Here we used Swiss mice to evaluate the acute toxicity profile of the six most promising anti-prionic compounds, the 2,4,5-trimethoxychalcones (J1, J8, J20 and J35) and the 1,3,4-oxadiazoles (Y13 and Y17). One single oral administration (300 mg/kg) of J1, J8, J20, J35, Y13 and Y17 or repeated intraperitoneal administration (10 mg/kg, 3 times a week, for 4 weeks) of J1, J8 and J35, did not elicit toxicity in mice. We strongly believe that the investigated trimethoxychalcones and oxadiazoles are interesting compounds to be further analyzed in vivo against prion diseases.

scholarly journals Adaptation and Selection of Prion Protein Strain Conformations following Interspecies Transmission of Transmissible Mink Encephalopathy

2000 ◽  
Vol 74 (12) ◽  
pp. 5542-5547 ◽  
Author(s):  
Jason C. Bartz ◽  
Richard A. Bessen ◽  
Debbie McKenzie ◽  
Richard F. Marsh ◽  
Judd M. Aiken
Keyword(s):  
Incubation Period ◽  
Prion Protein ◽  
Prion Diseases ◽  
Interspecies Transmission ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathy ◽  
Spongiform Encephalopathies ◽  
Strain Adaptation ◽  
Transmissible Mink Encephalopathy ◽  
Selection Of

ABSTRACT Interspecies transmission of the transmissible spongiform encephalopathies (TSEs), or prion diseases, can result in the adaptation and selection of TSE strains with an expanded host range and increased virulence such as in the case of bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease. To investigate TSE strain adaptation, we serially passaged a biological clone of transmissible mink encephalopathy (TME) into Syrian golden hamsters and examined the selection of distinct strain phenotypes and conformations of the disease-specific isoform of the prion protein (PrPSc). The long-incubation-period drowsy (DY) TME strain was the predominate strain, based on the presence of its strain-specific PrPSc following interspecies passage. Additional serial passages in hamsters resulted in the selection of the hyper (HY) TME PrPSc strain-dependent conformation and its short incubation period phenotype unless the passages were performed with a low-dose inoculum (e.g., 10−5 dilution), in which case the DY TME clinical phenotype continued to predominate. For both TME strains, the PrPSc strain pattern preceded stabilization of the TME strain phenotype. These findings demonstrate that interspecies transmission of a single cloned TSE strain resulted in adaptation of at least two strain-associated PrPScconformations that underwent selection until one type of PrPSc conformation and strain phenotype became predominant. To examine TME strain selection in the absence of host adaptation, hamsters were coinfected with hamster-adapted HY and DY TME. DY TME was able to interfere with the selection of the short-incubation HY TME phenotype. Coinfection could result in the DY TME phenotype and PrPSc conformation on first passage, but on subsequent passages, the disease pattern converted to HY TME. These findings indicate that during TSE strain adaptation, there is selection of a strain-specific PrPSc conformation that can determine the TSE strain phenotype.

scholarly journals Cells Expressing Anchorless Prion Protein Are Resistant to Scrapie Infection

2009 ◽  
Vol 83 (9) ◽  
pp. 4469-4475 ◽  
Author(s):  
Kristin L. McNally ◽  
Anne E. Ward ◽  
Suzette A. Priola
Keyword(s):  
Transgenic Mice ◽  
Prion Protein ◽  
Prion Diseases ◽  
Transmitted Disease ◽  
Transmissible Spongiform Encephalopathies ◽  
Gpi Anchor ◽  
Spongiform Encephalopathies ◽  
Infected Cells

ABSTRACT The hallmark of transmissible spongiform encephalopathies (TSEs or prion diseases) is the accumulation of an abnormally folded, partially protease-resistant form (PrP-res) of the normal protease-sensitive prion protein (PrP-sen). PrP-sen is attached to the cell membrane by a glycosylphosphatidylinositol (GPI) anchor. In vitro, the anchor and the local membrane environment are important for the conversion of PrP-sen to PrP-res. In vivo, however, the anchor is not necessary because transgenic mice expressing anchorless PrP-sen accumulate PrP-res and replicate infectivity. To clarify the role of the GPI anchor in TSE infection, cells expressing GPI-anchored PrP-sen, anchorless PrP-sen, or both forms of PrP-sen were exposed to the mouse scrapie strain 22L. Cells expressing anchored PrP-sen produced PrP-res after exposure to 22L. Surprisingly, while cells expressing anchorless PrP-sen made anchorless PrP-res in the first 96 h postinfection, no PrP-res was detected at later passes. In contrast, when cells expressing both forms of PrP-sen were exposed to 22L, both anchored and anchorless PrP-res were detected over multiple passes. Consistent with the in vitro data, scrapie-infected cells expressing anchored PrP-sen transmitted disease to mice whereas cells expressing anchorless PrP-sen alone did not. These results demonstrate that the GPI anchor on PrP-sen is important for the persistent infection of cells in vitro. Our data suggest that cells expressing anchorless PrP-sen are not directly infected with scrapie. Thus, PrP-res formation in transgenic mice expressing anchorless PrP-sen may be occurring extracellularly.

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