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crucial role for prion protein membrane anchoring in the neuroinvasion and neural spread of prion infection.in nature prion diseases are usually transmitted by extracerebral prion infection, but clinical disease results only after invasion of the central nervous system (cns). prion protein (prp), a host-encoded glycosylphosphatidylinositol (gpi)-anchored membrane glycoprotein, is necessary for prion infection and disease. here, we investigated the role of the anchoring of prp on prion neuroinvasion by studying various inoculation routes in mice expressing either anchored or anchorless prp. in control ...201021123371
heparin binding by murine recombinant prion protein leads to transient aggregation and formation of rna-resistant species.the conversion of cellular prion protein (prp(c)) into the pathological conformer prp(sc) requires contact between both isoforms and probably also requires a cellular factor, such as a nucleic acid or a glycosaminoglycan (gag). little is known about the structural features implicit in the gag-prp interaction. in the present work, light scattering, fluorescence, circular dichroism, and nuclear magnetic resonance (nmr) spectroscopy were used to describe the chemical and physical properties of the ...201021142149
the interaction of ruminant prp(sc) with soils is influenced by prion source and soil type.the persistence of prions within the environment is implicated in the horizontal transmission of ovine scrapie and cervid chronic wasting disease. description of the interaction of prion strains derived from their natural hosts with a range of soil types is imperative in understanding how prions persist in the environment and, therefore, the characteristics of prion transmission. here, we demonstrate that all detectable ovine scrapie and bovine bse prp(sc) bind to a range of soil types within 24 ...201020968294
comparison studies of the structural stability of rabbit prion protein with human and mouse prion proteins.prion diseases are fatal and infectious neurodegenerative diseases affecting humans and animals. rabbits are one of the few mammalian species reported to be resistant to infection from prion diseases isolated from other species (i. vorberg et al., journal of virology 77 (3) (2003) 2003-2009). thus the study of rabbit prion protein structure to obtain insight into the immunity of rabbits to prion diseases is very important.201020970434
a bayesian hierarchical analysis to compare classical and atypical scrapie surveillance data; wales 2002-2006.we describe the application of bayesian hierarchical models (bhm) to the analysis of risk of sheep scrapie using data from multiple surveillance sources. more specifically, we analysed data from the test results of three surveillance sources on classical and atypical scrapie in wales for the period 2002-2006. for each form of scrapie, a bhm was fitted to assess the occurrence of spatial patterns of risk shared by the multiple surveillance sources and the association between covariates and diseas ...201021040987
early embryonic gene expression profiling of zebrafish prion protein (prp2) morphants.the prion protein (prnp/prp) plays a crucial role in transmissible spongiform encephalopathies (tses) like creutzfeldt-jakob disease (cjd), scrapie and mad cow disease. notwithstanding the importance in human and animal disease, fundamental aspects of prnp/prp function and transmission remains unaccounted for.201021042590
enhanced enteric invasion of scrapie agents into the villous columnar epithelium via maternal immunoglobulin.transmissible spongiform encephalopathies (tse) are caused by dietary oral exposure to infectious prion proteins (prpsc); however, the mechanism behind the uptake of prpsc in the intestines is poorly understood. in addition, epidemiological studies of bse showed that most cattle are exposed to the agents in the first 6 months of life, during the suckling and weaning periods. in the present study, to elucidate the enteric invasion mechanism of prions and to investigate the age-dependent transmiss ...201021042778
ovine serum biomarkers of early and late phase scrapie.transmissible spongiform encephalopathies are fatal neurodegenerative disease occurring in animals and humans for which no ante-mortem diagnostic test in biological fluids is available. in such pathologies, detection of the pathological form of the prion protein (i.e., the causative factor) in blood is difficult and therefore identification of new biomarkers implicated in the pathway of prion infection is relevant.201021044301
prion protein self-interactions: a gateway to novel therapeutic strategies?transmissible spongiform encephalopathies (tses) or prion diseases are fatal neurodegenerative disorders and include among others creutzfeldt-jakob disease in humans, bovine spongiform encephalopathy (bse) in cattle, and scrapie in sheep. the central event in disease development in tses is the refolding of the normal host-encoded cellular prion protein (prp) into abnormal and disease associated prion protein. the agent is thought to consist mainly or exclusively of these pathologically folded pr ...201020932496
membrane interactions and conformational preferences of human and avian prion n-terminal tandem repeats: the role of copper(ii) ions, ph, and membrane mimicking environments.the flexible n-terminal domain of the prion protein (prp(c)) is believed to play a pivotal role in both trafficking of the protein through the cell membrane and its pathogenic conversion into the β sheet-rich scrapie isoform (prp(sc)). unlike mammalian prp(c), avian prion proteins are not known to undergo any pathogenic conformational conversions. consequently, some critical advances in our understanding of the molecular mechanisms underlying prion pathogenesis are expected from comparative stud ...201020936829
bse infectivity in the absence of detectable prp(sc) accumulation in the tongue and nasal mucosa of terminally diseased cattle.the pathogenesis of bovine spongiform encephalopathy (bse) infections in cattle has been studied in recent years by using highly sensitive transgenic-mouse bioassays. it has been shown that in this species, the bse agent amplifies almost exclusively in the central and peripheral nervous system. even in animals that were killed in the clinical end stage of the disease, the lymphoreticular system was shown to be free of the infectious agent. no other animal species investigated to date exhibits su ...201020943888
differentiation of ruminant transmissible spongiform encephalopathy isolate types, including bovine spongiform encephalopathy and ch1641 scrapie.with increased awareness of the diversity of transmissible spongiform encephalopathy (tse) strains in the ruminant population, comes an appreciation of the need for improved methods of differential diagnosis. exposure to bovine spongiform encephalopathy (bse) has been associated with the human tse, variant creutzfeldt-jakob disease, emphasizing the necessity in distinguishing low-risk tse types from bse. tse type discrimination in ruminants such as cattle, sheep, goats and deer, requires the app ...201020943889
a novel class of potential prion drugs: preliminary in vitro and in vivo data for multilayer coated gold nanoparticles.gold nanoparticles coated with oppositely charged polyelectrolytes, such as polyallylamine hydrochloride and polystyrenesulfonate, were examined for potential inhibition of prion protein aggregation and prion (prpsc) conversion and replication. different coatings, finishing with a positive or negative layer, were tested, and different numbers of layers were investigated for their ability to interact and reduce the accumulation of prpsc in scrapie prion infected scgt1 and scn2a cells. the particl ...201020944860
prion transmission: prion excretion and occurrence in the environment.prion diseases range from being highly infectious, for example scrapie and cwd, which show facile transmission between susceptible individuals, to showing negligible horizontal transmission, such as bse and cjd, which are spread via food or iatrogenically, respectively. scrapie and cwd display considerable in vivo dissemination, with prp(sc) and infectivity being found in a range of peripheral tissues. this in vivo dissemination appears to facilitate the recently reported excretion of prion thro ...201020948292
solution structure and dynamics of the i214v mutant of the rabbit prion protein.the conformational conversion of the host-derived cellular prion protein (prp(c)) into the disease-associated scrapie isoform (prp(sc)) is responsible for the pathogenesis of transmissible spongiform encephalopathies (tses). various single-point mutations in prp(c)s could cause structural changes and thereby distinctly influence the conformational conversion. elucidation of the differences between the wild-type rabbit prp(c) (raprp(c)) and various mutants would be of great help to understand the ...201020949107
sulfated dextrans enhance in vitro amplification of bovine spongiform encephalopathy prp(sc) and enable ultrasensitive detection of bovine prp(sc).prions, infectious agents associated with prion diseases such as creutzfeldt-jakob disease in humans, bovine spongiform encephalopathy (bse) in cattle, and scrapie in sheep and goats, are primarily comprised of prp(sc), a protease-resistant misfolded isoform of the cellular prion protein prp(c). protein misfolding cyclic amplification (pmca) is a highly sensitive technique used to detect minute amounts of scrapie prp(sc). however, the current pmca technique has been unsuccessful in achieving goo ...201020957174
prion replication in the hematopoietic compartment is not required for neuroinvasion in scrapie mouse model.fatal neurodegenerative prion diseases are caused by the transmissible prp(sc) prion agent whose initial replication after peripheral inoculation takes place in follicular dendritic cells present in germinal centers of lymphoid organs. however, prion replication also occurs in lymphoid cells. to assess the role of the hematopoietic compartment in neuroinvasion and prion replication, we generated chimeric mice, on a uniform congenic c57/bl6j background, by bone marrow replacement with hematopoiet ...201020957200
identification and structural analysis of c-terminally truncated collapsin response mediator protein-2 in a murine model of prion diseases.abstract:201020961402
molecular characterization of the full-length coding sequence of the caprine laminin receptor gene (rpsa).scrapie is a prion disease in sheep and goats. ribosomal protein sa (rpsa), also called 37 kda laminin receptor precursor/67 kda laminin receptor has been demonstrated to be a putative cell surface receptor for prion. to investigate the caprine rpsa, we cloned the full-length coding sequence of the gene of goat and submitted it to genbank. the length of the open reading frame is 888 bp, encoding 295 amino acids. the putative amino acid sequence is highly similar to that of other mammals. the cap ...201020839046
a new method for the characterization of strain-specific conformational stability of protease-sensitive and protease-resistant prp.although proteinacious in nature, prions exist as strains with specific self-perpetuating biological properties. prion strains are thought to be associated with different conformers of prp(sc), a disease-associated isoform of the host-encoded cellular protein (prp(c)). molecular strain typing approaches have been developed which rely on the characterization of protease-resistant prp(sc). however, prp(sc) is composed not only of protease-resistant but also of protease-sensitive isoforms. the aim ...201020856860
transcytosis of murine-adapted bovine spongiform encephalopathy agents in an in vitro bovine m cell model.transmissible spongiform encephalopathies (tse), including bovine spongiform encephalopathy (bse), are fatal neurodegenerative disorders in humans and animals. bse appears to have spread to cattle through the consumption of feed contaminated with bse/scrapie agents. in the case of an oral infection, the agents have to cross the gut-epithelial barrier. we recently established a bovine intestinal epithelial cell line (bie cells) that can differentiate into the m cell type in vitro after lymphocyti ...201020861256
cartilaginous metaplasia in the sclera of suffolk sheep.scleral cartilaginous metaplasia was detected by routine histologic examination of globes from 5 suffolk sheep from a scrapie pathogenesis study. the extent of the metaplasia varied among the sheep but was always posterior to the tapetal fundus. the matrix surrounding chondrocytes stained intensely with alcian blue and was immunopositive for type ii collagen. retrospective evaluation of additional eyes from suffolk and cheviot sheep used in various scrapie pathogenesis studies at the authors' fa ...201020861498
capacity of the manufacturing process of flebogamma(®) dif, a new human high purity intravenous immunoglobulin, to remove a tse model-agent.the variant creutfeldt-jakob disease (vcjd) is a transmissible spongiform encephalopathy (tse) associated with the ingestion of cattle derived products affected with bovine spongiform encephalopathy. vcjd emerged in the uk, where most of the cases occurred (170 of 217 cases worldwide). manufacturers of biological products must investigate the ability of their production processes to remove tse agents. two manufacturing steps (polyethylene glycol-peg precipitation and nanofiltration down to 20 nm ...201020863716
amyloid structure and assembly: insights from scanning transmission electron microscopy.amyloid fibrils are filamentous protein aggregates implicated in several common diseases such as alzheimer's disease and type ii diabetes. similar structures are also the molecular principle of the infectious spongiform encephalopathies such as creutzfeldt-jakob disease in humans, scrapie in sheep, and of the so-called yeast prions, inherited non-chromosomal elements found in yeast and fungi. scanning transmission electron microscopy (stem) is often used to delineate the assembly mechanism and s ...201020868754
marked influence of the route of infection on prion strain apparent phenotype in a scrapie transgenic mouse model.prion strains yield specific neuropathological features including spongiform degeneration and deposition patterns of pathological prion protein. their invariant regional distribution, following variations in the infection route, has led to the proposal that prions replicate preferentially in defined neuro-anatomical areas. the molecular mechanisms underlying this apparent strain-specific neuronal tropism are currently unknown. however, a possible explanation may be that prion replication is rela ...201020875860
prion genotypes of scrapie-infected canadian sheep 1998-2008.this report describes the genetics of the prion protein gene (prnp) at codons 136, 154, and 171 for sheep diagnosed with naturally acquired classical scrapie in canada between 1998 and 2008. genotyping analysis was performed on 249 sheep with confirmed classical scrapie infection representing 98 flocks from 6 provinces. a further case-control analysis of 3 of these flocks compared the genotypes between infected sheep (n = 72) and those of their healthy flockmates (n = 1990). the incidence of cla ...201020885849
plasminogen stimulates propagation of protease-resistant prion protein in vitro.to clarify the role of plasminogen as a cofactor for prion propagation, we conducted functional assays using a cell-free prion protein (prp) conversion assay termed protein misfolding cyclic amplification (pmca) and prion-infected cell lines. here, we report that plasminogen stimulates propagation of the protease-resistant scrapie prp (prp(sc)). compared to control pmca conducted without plasminogen, addition of plasminogen in pmca using wild-type brain material significantly increased prp conve ...201020732953
environmental sources of scrapie prions.ovine scrapie and cervine chronic wasting disease show considerable horizontal transmission. here we report that a scrapie-affected sheep farm has a widespread environmental contamination with prions. prions were amplified by protein-misfolding cyclic amplification (spmca) from seven of nine environmental swab samples taken, including those from metal, plastic, and wooden surfaces. sheep had been removed from the areas from which the swabs were taken up to 20 days prior to sampling, indicating t ...201020739536
synthesis and anti-prion activity evaluation of aminoquinoline analogues.transmissible spongiform encephalopathies form a group of neurodegenerative diseases that affect humans and other mammals. they occur when the native prion protein is converted into an infectious isoform, the scrapie prp, which aggregates, leading to neurodegeneration. although several compounds were evaluated for their ability to inhibit this conversion, there is no effective therapy for such diseases. previous studies have shown that antimalarial compounds, such as quinolines, possess anti-scr ...201020797807
detection of prp(sc) in formalin-fixed, paraffin-embedded tissue by western blot differentiates classical scrapie, nor98 scrapie, and bovine spongiform encephalopathy.transmissible, spongiform encephalopathies including bovine spongiform encephalopathy (bse) and scrapie are fatal neurodegenerative disorders associated with the presence of an infectious abnormal isoform of normal mammalian proteins called prions. identification of the prion protein associated with scrapie (prp(sc)) in the central nervous system is typically based upon immunoassays including immunohistochemistry (ihc) using formalin-fixed tissues or western blot (wb) assays using fresh and/or f ...201020807921
sequence-dependent prion protein misfolding and neurotoxicity.prion diseases are neurodegenerative disorders caused by misfolding of the normal prion protein (prp) into a pathogenic "scrapie" conformation. to better understand the cellular and molecular mechanisms that govern the conformational changes (conversion) of prp, we compared the dynamics of prp from mammals susceptible (hamster and mouse) and resistant (rabbit) to prion diseases in transgenic flies. we recently showed that hamster prp induces spongiform degeneration and accumulates into highly ag ...201020817727
digestion and transportation of bovine spongiform encephalopathy-derived prion protein in the sheep intestine.bovine spongiform encephalopathy (bse) is acquired orally and the mechanisms involved in the absorption and transportation of infectivity across the gut wall are therefore critical. isolated gut loops were created in lambs, massaged to remove intestinal contents (flushed) or left non-flushed, inoculated with cattle bse homogenate and excised at different time-points. gut loops were examined by immunohistochemistry (ihc) for disease-associated prion protein (prp(d)), and the contents were analyse ...201020826616
prion strain interactions are highly selective.various misfolded and aggregated neuronal proteins commonly coexist in neurodegenerative disease, but whether the proteins coaggregate and alter the disease pathogenesis is unclear. here, we used mixtures of distinct prion strains, which are believed to differ in conformation, to test the hypothesis that two different aggregates interact and change the disease in vivo. we tracked two prion strains in mice histopathologically and biochemically, as well as by spectral analysis of plaque-bound ptaa ...201020826672
a drosophila model of gss syndrome suggests defects in active zones are responsible for pathogenesis of gss syndrome.we have established a drosophila model of gerstmann-sträussler-scheinker (gss) syndrome by expressing mouse prion protein (prp) having leucine substitution at residue 101 (moprp(p101l)). flies expressing moprp(p101l), but not wild-type moprp (moprp(3f4)), showed severe defects in climbing ability and early death. expressed moprp(p101l) in drosophila was differentially glycosylated, localized at the synaptic terminals and mainly present as deposits in adult brains. we found that behavioral defect ...201020829230
transport of the pathogenic prion protein through soils.transmissible spongiform encephalopathies (tses) are progressive neurodegenerative diseases and include bovine spongiform encephalopathy of cattle, chronic wasting disease (cwd) of deer and elk, scrapie in sheep and goats, and creutzfeldt-jakob disease in humans. an abnormally folded form of the prion protein (designated prp(tse)) is typically associated with tse infectivity and may constitute the major, if not sole, component of the infectious agent. transmission of cwd and scrapie is mediated ...201020830901
early noninvasive diagnosis of neurodegenerative diseases.this paper reviews the contemporary trends in the pathobiochemistry of neurodegenerative disorders with respect to their early predictive diagnosis and possible treatment interventions. if we consider the current epidemiological data related to neurodegenerative disorders, medicine is going to face in the near future latent pandemic situations. the introduction puts an emphasis on the emerging importance of one major cluster of neurodegenerative disorders: diseases of the abnormal protein beta-c ...201020836391
a "shotgun" method for tracing the birth locations of sheep from flock tags, applied to scrapie surveillance in great britain.movement records are often used to identify animal sample provenance by retracing the movements of individuals. here we present an alternative method, which uses the same identity tags and movement records as are used to retrace movements, but ignores individual movement paths. the first step uses a simple query to identify the most likely birth holding for every identity tag included in a database recording departures from agricultural holdings. the second step rejects a proportion of the birth ...201020692059
aberrant erk 1/2 complex activation and localization in scrapie-infected gt1-1 cells.abstract:201020696038
variability in disease phenotypes within a single prnp genotype suggests the existence of multiple natural sheep scrapie strains within europe.variability of pathological phenotypes within classical sheep scrapie cases has been reported for some time, but in many instances it has been attributed to differences in the prnp genotype of the host. to address this issue we have examined by immunohistochemistry (ihc) and western blotting (wb) for the disease-associated form of the prion protein (prp(d)), the brains of 23 sheep from five european countries, all of which were of the same arq/arq genotype. as a result of ihc examinations, sheep ...201020538906
immunohistochemical study of macrophage and cytokine dynamics in the gut of scrapie-infected mice.to study numerical changes in intestinal macrophages and variations in cytokine production by immune cells in the intestine, conventional c57bl/6j mice were orally infected with the rocky mountain laboratory strain of scrapie. animals were sacrificed at different timepoints, and samples were taken and processed by routine methods for morphological and immunohistochemical analysis. the results point to a possible role for macrophages in the uptake and transport of the infective agent to peyer's p ...201020552553
sensitive detection of scrapie prion protein in soil.prion diseases are fatal neurodegenerative disorders that are caused by infectious agents known as prions. prions are composed primarily of the pathogenic prion protein isoform, prp(sc). because significant levels of infectivity have been detected in excrement from animals infected with scrapie and chronic wasting disease, studies on the dynamics of prp(sc) levels in contaminated soil are needed to assess the possible horizontal transmission of prion diseases. using protein misfolding cyclic amp ...201020570651
use of a preclinical test in the control of classical scrapie.scrapie control in great britain (gb) was originally based on the national scrapie plan's ram genotyping scheme aimed at reducing the susceptibility of the national flock. the current official strategy to control scrapie in the national flock involves culling susceptible genotypes in individual, known affected flocks (compulsory scrapie flock scheme or csfs). however, the recent development of preclinical test candidates means that a strategy based on disease detection may now be feasible. here, ...201020573855
sex effect in mouse and human prion disease.sex effect on the incubation period of variant creutzfeldt-jakob disease (vcjd) disease in human and me-7 murine models was investigated. in the 167 vcjd cases reported in the united kingdom as of january 2009, age at onset was significantly lower in female patients (by 2 years) than in male patients after stratification on birth cohort. in c57/bl6n mice infected with me-7 scrapie strain, incubation was shorter in female than in male mice. the incubation period increased in castrated male mice a ...201020594106
the discovery of misfolded prions as an infectious agent. 201020594190
prion interaction with the 37-kda/67-kda laminin receptor on enterocytes as a cellular model for intestinal uptake of prions.enterocytes, a major cell population of the intestinal epithelium, represent one possible barrier to the entry of prions after oral exposure. we established a cell culture system employing enterocytes from different species to study alimentary prion interaction with the 37-kda/67-kda laminin receptor lrp/lr. human, bovine, porcine, ovine, and cervid enterocytes were cocultured with brain homogenates from cervid, sheep, and cattle suffering from chronic wasting disease (cwd), scrapie, and bovine ...201020603132
risk of escape of prions in gaseous emissions from on-farm digestion vessels. 201020605957
[cellular prion protein in the central nervous system of mammals. anatomoclinical associations].the scrapie prion protein (prpsc) requires the cellular prion protein (prpc) for its propagation and replication. in this work we studied the expression and localization of the prpc in the central nervous system (snc) of the rat, mouse, cat, cow and human, using immunohistochemistry and western blot techniques to understand more about prionopathies and alzheimer's disease (ea).201020609300
a case-control study of atypical scrapie in gb sheep flocks.wide-scale scrapie surveillance started in 2002 in the eu. as a result, a new form of scrapie was detected which has been referred to as atypical scrapie. here we present a case-control study conducted on british sheep farms to increase our understanding of the disease and potential risk factors at holding level. forty case and 120 control holdings were traced from the confirmed atypical results in the scrapie surveillance programme in great britain during the period 2002-2007. a detailed questi ...201020615563
paradoxical role of prion protein aggregates in redox-iron induced toxicity.imbalance of iron homeostasis has been reported in sporadic creutzfeldt-jakob-disease (scjd) affected human and scrapie infected animal brains, but the contribution of this phenotype to disease associated neurotoxicity is unclear.201020625431
prp(sc) is associated with b cells in the blood of scrapie-infected sheep.recently, we reported that prp(sc), a surrogate marker for prion disease, is associated with the cellular fraction of blood from scrapie-infected sheep using a ligand-based immunoassay. in the study reported here, we found that a subset of peripheral blood mononuclear cells is most likely to sequester prp(sc) during both the preclinical phase of disease and at clinical end point. these cells had a cell surface phenotype of mhc class ii dq(+), surface immunoglobulin(+), cd11b(+), cd11c(+), cd21(+ ...201020646730
neuroinvasion in prion diseases: the roles of ascending neural infection and blood dissemination.prion disorders are infectious, neurodegenerative diseases that affect humans and animals. susceptibility to some prion diseases such as kuru or the new variant of creutzfeldt-jakob disease in humans and scrapie in sheep and goats is influenced by polymorphisms of the coding region of the prion protein gene, while other prion disorders such as fatal familial insomnia, familial creutzfeldt-jakob disease, or gerstmann-straussler-scheinker disease in humans have an underlying inherited genetic basi ...201020652006
biochemical and immunohistochemical characterization of feline spongiform encephalopathy in a german captive cheetah.feline spongiform encephalopathy (fse) is a transmissible spongiform encephalopathy that affects domestic cats (felis catus) and captive wild members of the family felidae. in this report we describe a case of fse in a captive cheetah from the zoological garden of nuremberg. the biochemical examination revealed a bse-like pattern. disease-associated scrapie prion protein (prp(sc)) was widely distributed in the central and peripheral nervous system, as well as in the lymphoreticular system and in ...201020660146
spontaneous generation of mammalian prions.prions are transmissible agents that cause lethal neurodegeneration in humans and other mammals. prions bind avidly to metal surfaces such as steel wires and, when surface-bound, can initiate infection of brain or cultured cells with remarkable efficiency. while investigating the properties of metal-bound prions by using the scrapie cell assay to measure infectivity, we observed, at low frequency, positive assay results in control groups in which metal wires had been coated with uninfected mouse ...201020660771
nmr structure of the human prion protein with the pathological q212p mutation reveals unique structural features.prion diseases are fatal neurodegenerative disorders caused by an aberrant accumulation of the misfolded cellular prion protein (prp(c)) conformer, denoted as infectious scrapie isoform or prp(sc). in inherited human prion diseases, mutations in the open reading frame of the prp gene (prnp) are hypothesized to favor spontaneous generation of prp(sc) in specific brain regions leading to neuronal cell degeneration and death. here, we describe the nmr solution structure of the truncated recombinant ...201020661422
beta-sheet constitution of prion proteins.structural information regarding normal prion protein (prp(c)) and the scrapie isoform (prp(sc)) is of vital importance for elucidating the pathogenesis of prion diseases (pds). despite successful determination of the three-dimensional structures of prp(c), the structural details of prp(sc) remain elusive. nevertheless, accumulated evidence indicates that beta-sheets comprise the basic building blocks of prp(sc). consensus has been reached about the beta-sheet constitution of the n-terminus of p ...201020060302
consequences of dietary manganese and copper imbalance on neuronal apoptosis in a murine model of scrapie.copper and manganese levels are altered in mice both lacking prpc and prion-infected brains. the aim of this study was to analyse the effects of manganese and copper imbalance on neuronal apoptosis in a scrapie-infected tga20 mouse model.201020070537
association of endothelial nitric oxide synthase and mitochondrial dysfunction in the hippocampus of scrapie-infected mice.the elevation of nitric oxide (no) within the central nervous system (cns) is known to be associated with the pathogenesis of neurodegenerative diseases such as hiv-associated dementia (had), brain ischemia, parkinson's disease, and alzheimer's disease. no is enzymatically formed by the enzyme nitric oxide synthase (nos). there are two forms of nos, the constitutive and the inducible form. the constitutive form is present in endothelial cells (enos) and neurons (nnos). the inducible form (inos) ...201020082297
differentiating blood samples from scrapie infected and non-infected hamsters by detecting disease-associated prion proteins using multimer detection system.this communication describes the application of a modified sandwich enzyme-linked immunosorbent assay (elisa), termed multimer detection system (mds) for the detection of disease-associated multimeric forms of the prion protein (prpd) in hamster blood. prpd was detected in plasma of prion-affected hamsters while mds revealed no prpd in identically-treated plasma of healthy animals. this is the first report of a single elisa- based immune detection of prpd from blood samples.201020085753
involvement of peptidylarginine deiminase-mediated post-translational citrullination in pathogenesis of sporadic creutzfeldt-jakob disease.peptidylarginine deiminases (pads)-mediated post-translational citrullination processes play key roles in protein functions and structural stability through the conversion of arginine to citrulline in the presence of excessive calcium concentrations. in brain, pad2 is abundantly expressed and can be involved in citrullination in disease. recently, we have reported pathological characterization of pad2 and citrullinated proteins in scrapie-infected mice, but the implication of protein citrullinat ...201020013286
effect of scrapie on the stability of housekeeping genes.scrapie is the archetype of prion diseases, fatal neurodegenerative disorders that affect humans and animals. gene expression analysis of normal and infected sheep may provide clues to clarify the molecular mechanisms involved in the neuropathology of these diseases. real time quantitative pcr has become a powerful and accurate technique for examination of transcription patterns in different biological conditions. one of the critical steps in the comparison of transcription profiles is the selec ...201020024782
co-existence of classical scrapie and nor98 in a sheep from an italian outbreak.nor98 is an atypical scrapie strain characterized by a molecular pattern and brain distribution of the pathological prion protein (prp(sc)) different from classical scrapie. in italy, 69 atypical cases have been identified so far and all were characterized as nor98 strain. in this paper we report an unusual case in a sheep which showed immunohistochemical and molecular features of prp(sc) different from the other atypical cases. the sheep was from an outbreak where the index and the other four c ...201020031179
infection of cell lines with experimental and natural ovine scrapie agents.mouse bioassay remains the gold standard for determining proof of infectivity, strain type, and infectious titer estimation in prion disease research. the development of an approach using ex vivo cell-based assays remains an attractive alternative, both in order to reduce the use of mice and to hasten results. the main limitation of a cell-based approach is the scarcity of cell lines permissive to infection with natural transmissible spongiform encephalopathy strains. this study combines two adv ...201020032176
amino acid conditions near the gpi anchor attachment site of prion protein for the conversion and the gpi anchoring.prion protein (prp) is a glycosylphosphatidylinositol (gpi)-anchored protein, and the c-terminal gpi anchor signal sequence (gpi-ss) of prp is cleaved before gpi anchoring. however, mutations near the gpi anchor attachment site (the omega site) in the gpi-ss have been recognized in human genetic prion diseases. moreover, the omega site of prp has not been identified except hamster, though it is known that amino acid restrictions are very severe at the omega and omega+2 sites in other gpi-anchore ...201020040362
degradation and destabilization of abnormal prion protein using alkaline detergents and proteases.there is a limited number of reports regarding detergents and proteases inactivating, degrading, or destabilizing abnormal prion protein (prpsc). in the present study, the effect of alkaline detergents and proteases on the breakdown of prpsc in the absence of proteinase k (pk) (degradation) and the presence of pk (destabilization) was investigated. prpsc from brain homogenate of terminally-diseased mice infected with the chandler strain of scrapie was used as a substrate. a surfactant-free alkal ...201020043137
detection of prpsc in lung and mammary gland is favored by the presence of visna/maedi virus lesions in naturally coinfected sheep.there are few reports on the pathogenesis of scrapie (sc) and visna/maedi virus (vmv) coinfections. the aim of this work was to study in vivo as well as post mortem both diseases in 91 sheep. diagnosis of sc and vmv infections allowed the distribution of animals into five groups according to the presence (+) or absence (-) of infection by sc and vmv: sc-/vmv-, sc-/vmv+, sc+/vmv- and sc+/vmv+. the latter was divided into two subgroups, with and without vmv-induced lymphoid follicle hyperplasia (l ...201020423698
glycosylphosphatidylinositol anchor analogues sequester cholesterol and reduce prion formation.a hallmark of prion diseases is the conversion of the host-encoded prion protein (prp(c) where c is cellular) into an alternatively folded, disease-related isoform (prp(sc), where sc is scrapie), the accumulation of which is associated with synapse degeneration and ultimately neuronal death. the formation of prp(sc) is dependent upon the presence of prp(c) in specific, cholesterol-sensitive membrane microdomains, commonly called lipid rafts. prp(c) is targeted to these lipid rafts because it is ...201020427265
iron content of ferritin modulates its uptake by intestinal epithelium: implications for co-transport of prions.the spread of chronic wasting disease (cwd) in the deer and elk population has caused serious public health concerns due to its potential to infect farm animals and humans. like other prion disorders such a sporadic creutzfeldt-jakob-disease of humans and mad cow disease of cattle, cwd is caused by prp-scrapie (prpsc), a beta-sheet rich isoform of a normal cell surface glycoprotein, the prion protein (prpc). since prpsc is sufficient to cause infection and neurotoxicity if ingested by a suscepti ...201020429907
ovine reference materials and assays for prion genetic testing.genetic predisposition to scrapie in sheep is associated with several variations in the peptide sequence of the prion protein gene (prnp). dna-based tests for scoring prnp codons are essential tools for eradicating scrapie and for evaluating rare alleles for increased resistance to disease. in addition to those associated with scrapie, there are dozens more prnp polymorphisms that may occur in various flocks. if not accounted for, these sites may cause base-pair mismatching with oligonucleotides ...201020433741
prions of ruminants show distinct splenotropisms in an ovine transgenic mouse model.transmissible agents involved in prion diseases differ in their capacities to target different regions of the central nervous system and lymphoid tissues, which are also host-dependent.201020436680
eradication of scrapie with selective breeding: are we nearly there?following eu decision 2003/100/ec member states have recently implemented sheep breeding programmes to reduce the prevalence of sheep with tse susceptible prion genotypes. the present paper investigates the progress of the breeding programme in the netherlands. the prp genotype frequencies were monitored through time using two sets of random samples: one set covers the years 2005 to 2008 and is taken from national surveillance programme; the other is taken from 168 random sheep farms in 2007. th ...201020441587
relevance of oral experimental challenge with classical scrapie in sheep.oral inoculation is currently considered as the best approach to mimic natural tse contamination in ruminants. in this study, we compared the timing of abnormal prion protein (prp(sc)) dissemination and accumulation in the organism of susceptible sheep either orally inoculated or naturally infected with classical scrapie. both animal groups shared a similar prp(sc) dissemination scheme and accumulation dynamics in lymphoid tissues. however, orally challenged animals displayed an earlier neuro-in ...201020444991
enzymatic digestion of chronic wasting disease prions bound to soil.chronic wasting disease (cwd) and sheep scrapie can be transmitted via indirect environmental routes, and it is known that soil can serve as a reservoir of prion infectivity. given the strong interaction between the prion protein (prp) and soil, we hypothesized that binding to soil enhances prion resistance to enzymatic digestion, thereby facilitating prion longevity in the environment and providing protection from host degradation. we characterized the performance of a commercially available su ...201020450190
identification of atypical scrapie in canadian sheep.scrapie, a transmissible spongiform encephalopathy of sheep and goats, exists in most small ruminant-producing countries of the world. a novel form of this disease was recently recognized and is known by various names, including nor98, nor98-like, and atypical scrapie. differing from classic scrapie in epidemiology, histopathology, and biochemical characteristics, atypical scrapie cases have been identified throughout europe and in the united states. enhanced scrapie surveillance efforts recentl ...201020453215
horse prion protein nmr structure and comparisons with related variants of the mouse prion protein.the nmr structure of the horse (equus caballus) cellular prion protein at 25 degrees c exhibits the typical prp(c) [cellular form of prion protein (prp)] global architecture, but in contrast to most other mammalian prp(c)s, it contains a well-structured loop connecting the beta2 strand with the alpha2 helix. comparison with designed variants of the mouse prion protein resulted in the identification of a single amino acid exchange within the loop, d167s, which correlates with the high structural ...201020460128
association of n176k and l141f dimorphisms of the prnp gene with lack of pathological prion protein deposition in placentas of naturally and experimentally scrapie-affected arq/arq sheep.the placenta is important in the horizontal transmission of the aetiological agent in scrapie-affected sheep. it has been demonstrated that the placentas of fetuses carrying the dimorphism q171r of the prnp gene is resistant to pathological prion protein (prp(sc)) accumulation in the placenta. to test whether other prnp polymorphisms are associated with a lack of placental prp(sc) deposition, we carried out a study on 26 naturally and 11 experimentally scrapie-affected ewes with or without clini ...201020463148
scrapie prevalence in sheep of susceptible genotype is declining in a population subject to breeding for resistance.susceptibility of sheep to scrapie infection is known to be modulated by the prp genotype of the animal. in the netherlands an ambitious scrapie control programme was started in 1998, based on genetic selection of animals for breeding. from 2002 onwards eu regulations required intensive active scrapie surveillance as well as certain control measures in affected flocks.here we analyze the data on genotype frequencies and scrapie prevalence in the dutch sheep population obtained from both surveill ...201020470415
quantitative estimation of genetic risk for atypical scrapie in french sheep and potential consequences of the current breeding programme for resistance to scrapie on the risk of atypical scrapie.since 2002, active surveillance programmes have detected numerous atypical scrapie (as) and classical scrapie cases (cs) in french sheep with almost all the prp genotypes. the aim of this study was 1) to quantify the genetic risk of as in french sheep and to compare it with the risk of cs, 2) to quantify the risk of as associated with the increase of the arr allele frequency as a result of the current genetic breeding programme against cs.201020482755
the distribution of four trace elements (fe, mn, cu, zn) in forage and the relation to scrapie in iceland.previous studies indicated that the iron (fe)/manganese (mn) ratio in forage of sheep was significantly higher on scrapie-afflicted farms than on farms in other scrapie categories. this study was conducted to examine whether fe and mn in forage of sheep varied in general according to the scrapie status of different areas in the country. copper (cu) and zinc (zn) were also included because of a possible relation to scrapie.201020492671
calnexin inhibits thermal aggregation and neurotoxicity of prion protein.prion diseases are fatal neurodegenerative disorder associated with the conversion of the cellular isoform of the prion protein (prp(c)) into the infectious scrapie isoform (prp(sc)). deposition of misfolded prion proteins (prp) on certain regions of brain can result in prion diseases. as a membrane-bound chaperone of the endoplasmic reticulum (er), calnexin ensures the proper folding and quality control of newly synthesized proteins. using purified components in vitro, calnexin associated with ...201020506117
estimating prion concentration in fluids and tissues by quantitative pmca.prions, the proteinaceous infectious agent responsible for prion diseases, can be detected with high sensitivity by protein misfolding cyclic amplification (pmca) technology. here we describe a quantitative pmca procedure to calculate the concentration of very low levels of prions in biological samples. using this procedure, we determined the quantities of misfolded prion protein (prp(sc)) in brain, spleen, blood and urine of scrapie-affected hamsters.201020512142
comparative profiling of highly enriched 22l and chandler mouse scrapie prion protein preparations.transmissible spongiform encephalopathies (tses) or prion diseases are characterized by the accumulation of an aggregated isoform of the prion protein (prp). this pathological isoform, termed prp(sc), appears to be the primary component of the tse infectious agent or prion. however, it is not clear to what extent other protein cofactors may be involved in tse pathogenesis or whether there are prp(sc)-associated proteins which help to determine tse strain-specific disease phenotypes. we enriched ...201020518029
cell-based quantification of chronic wasting disease prions.cell-based measurement of prion infectivity is currently restricted to experimental strains of mouse-adapted scrapie. having isolated cell cultures with susceptibility to prions from diseased elk, we describe a modification of the scrapie cell assay allowing evaluation of prions causing chronic wasting disease, a naturally occurring transmissible spongiform encephalopathy. we compare this cervid prion cell assay to bioassays in transgenic mice, the only other existing method for quantification, ...201020519392
prion protein misfolding affects calcium homeostasis and sensitizes cells to endoplasmic reticulum stress.prion-related disorders (prds) are fatal neurodegenerative disorders characterized by progressive neuronal impairment as well as the accumulation of an abnormally folded and protease resistant form of the cellular prion protein, termed prp(res). altered endoplasmic reticulum (er) homeostasis is associated with the occurrence of neurodegeneration in sporadic, infectious and familial forms of prds. the er operates as a major intracellular calcium store, playing a crucial role in pathological event ...201021209925
the effects of lysosomal and proteasomal inhibitors on abnormal forms of prion protein degradation in murine macrophages.it has been reported that macrophages degrade infectious forms of prion protein (prp(sc) ). in order to investigate the mechanisms underlying prp(sc) degradation in macrophages, the effects of lysosomal and proteasomal inhibitors on macrophage cell lines which were incubated with scrapie-affected brain homogenate were studied. prp(sc) degradation was inhibited in the presence of both proteasomal and lysosomal inhibitors. indirect fluorescence assays to determine the cellular localization of prp( ...201021223366
iatrogenic concerns of the twentieth century: post-vaccinal encephalitis and spongiform encephalopathy.throughout the twentieth century, iatrogenic disease constituted an enduring problem in western medical discourse and practice. a survey of the medical literature, investigative reports, and archival material indicates that iatrogenic concerns persisted throughout the century. two groups of case studies are presented: one associated with post-vaccinal encephalitis; the other, with the iatrogenically transmitted spongiform encephalopathies, scrapie and creutzfeldt-jakob disease. kuru, a similar d ...201021553697
high-resolution differentiation of transmissible spongiform encephalopathy strains by quantitative n-terminal amino acid profiling (n-taap) of pk-digested abnormal prion protein.new forms of transmissible spongiform encephalopathy (tse) continue to be identified, and consequently sensitive differential diagnosis is increasingly important both for the management of disease in humans and livestock and in providing confidence in the safety of the food chain. tse diseases are associated with accumulation of protease-resistant prion protein (prp(sc)) and detection of this marker protein is central to diagnosis. proteolysis by proteinase k (pk) generates protease-resistant pr ...200919053160
prions are secreted in milk from clinically normal scrapie-exposed sheep.the potential spread of prion infectivity in secreta is a crucial concern for prion disease transmission. here, serial protein misfolding cyclic amplification (spmca) allowed the detection of prions in milk from clinically affected animals as well as scrapie-exposed sheep at least 20 months before clinical onset of disease, irrespective of the immunohistochemical detection of protease-resistant prp(sc) within lymphoreticular and central nervous system tissues. these data indicate the secretion o ...200919494004
two unusual bovine spongiform encephalopathy cases detected in great britain.bovine spongiform encephalopathy (bse) was first identified in great britain (gb) in 1986 and was subsequently detected in many other countries, worldwide. a decade after the start of the bovine epidemic, the first cases of new variant creutzfeldt-jakob disease (vcjd) in humans were linked to probable ingestion of bse infected tissue, highlighting a new zoonotic disease. an abnormal protease-resistant protein (prp(res)) in a diseased subject, derived from a post-translational change of a normal ...200919497088
state-of-the-art review of goat tse in the european union, with special emphasis on prnp genetics and epidemiology.scrapie is a fatal, neurodegenerative disease of sheep and goats. it is also the earliest known member in the family of diseases classified as transmissible spongiform encephalopathies (tse) or prion diseases, which includes creutzfeldt-jakob disease in humans, bovine spongiform encephalopathy (bse), and chronic wasting disease in cervids. the recent revelation of naturally occurring bse in a goat has brought the issue of tse in goats to the attention of the public. in contrast to scrapie, bse p ...200919505422
shadoo (sprn) and prion disease incubation time in mice.prion diseases are transmissible neurodegenerative disorders of mammalian species and include scrapie, bovine spongiform encephalopathy (bse), and variant creutzfeldt-jakob disease (vcjd). the prion protein (prp) plays a key role in the disease, with coding polymorphism in both human and mouse influencing disease susceptibility and incubation time, respectively. other genes are also thought to be important and a plausible candidate is sprn, which encodes the prp-like protein shadoo (sho). sho is ...200919513788
immunohistochemical characterisation of classical scrapie neuropathology in sheep.neuroinflammation elicited by prp(res) (resistant prion protein [prp]) deposits in the central nervous system (cns) has been shown to involve cellular and oxidative stress responses in bovine spongiform encephalopathy (bse) as well as in several murine models of transmissible spongiform encephalopathy (tse). additionally, deregulation of water homeostasis has been suggested to be a further component of the spongiform changes observed in tses. the aim of the present study was to characterize the ...200919515381
genetic analysis of the sprn gene in ruminants reveals polymorphisms in the alanine-rich segment of shadoo protein.prion diseases in ruminants, especially sheep scrapie, cannot be fully explained by prnp genetics, suggesting the influence of a second modulator gene. the sprn gene is a good candidate for this role. the sprn gene encodes the shadoo protein (sho) which has homology to the prnp gene encoding prion protein (prp). murine sho has a similar neuroprotective activity to prp and sprn gene variants are associated with human prion disease susceptibility. sprn gene sequences were obtained from 14 species ...200919515828
comparative prion disease gene expression profiling using the prion disease mimetic, cuprizone.identification of genes expressed in response to prion infection may elucidate biomarkers for disease, identify factors involved in agent replication, mechanisms of neuropathology and therapeutic targets. although several groups have sought to identify gene expression changes specific to prion disease, expression profiles rife with cell population changes have consistently been identified. cuprizone, a neurotoxicant, qualitatively mimics the cell population changes observed in prion disease, res ...200919535908
variable levels of 37-kda/67-kda laminin receptor (rpsa) mrna in ovine tissues: potential contribution to the regulatory processes of prpsc propagation?the 37-kda laminin receptor precursor/67-kda laminin receptor (lrp/lr, also known as ribosomal protein sa, rpsa) has been reported to be involved in cancer development and prion internalization. previous studies have shown that the lrp/lr is expressed in a wide variety of tissues. in particular, expression of lrp/lr mrna may be closely related to the degree of prp(sc) propagation. this study presents a detailed investigation of the lrp/lr mrna expression levels in eleven normal ovine tissues. us ...200919544211
prion removal effect of a specific affinity ligand introduced into the manufacturing process of the pharmaceutical quality solvent/detergent (s/d)-treated plasma octaplaslg.a new chromatographic step for the selective binding of abnormal prion protein (prp(sc)) was developed, and optimization for prp(sc) capture was achieved by binding to an affinity ligand attached to synthetic resin particles. this step was implemented into the manufacturing process of the solvent/detergent (s/d)-treated biopharmaceutical quality plasma octaplas to further improve the safety margin in terms of risk for variant creutzfeldt-jakob disease (vcjd) transmission.200919548963
the cellular prion protein and its role in alzheimer disease.the cellular prion protein (prp(c)) is a membrane-bound glycoprotein especially abundant in the central nervous system (cns). the scrapie prion protein (prp(sc,) also termed prions) is responsible of transmissible spongiform encephalopathies (tse), a group of neurodegenerative diseases which affect humans and other mammal species, although the presence of prp(c) is needed for the establishment and further evolution of prions. the present work compares the expression and localization of prp(c) be ...200919556894
design and validation of a high-throughput assay to detect codon 146 polymorphisms in the caprine prion protein gene.in sheep, scrapie susceptibility is so strongly associated with single nucleotide polymorphisms (snps) in the gene encoding the prion protein (prp) that this linkage constitutes the basis for selective breeding strategies directed toward controlling the disease. for goats, in contrast, the association between scrapie susceptibility/resistance and variations in the prp gene is far weaker, with only a few identified snps showing an influence on scrapie susceptibility. a recent survey of prp genoty ...200919559665
elimination capacity of a tse-model agent in the manufacturing process of alphanate/fanhdi, a human factor viii/vwf complex concentrate.the variant creutzfeldt-jakob disease (vcjd) is a transmissible spongiform encephalopathy (tse), mainly present in the uk and is associated with the ingestion of bovine products affected with bovine spongiform encephalopathy. manufacturers of biological products must investigate the ability of their production processes to remove tse agents. we studied the purification steps in the manufacturing process of two fviii/vwf concentrates (alphanate) and fanhdi in their ability to eliminate an experim ...200919563480
role of adams in the ectodomain shedding and conformational conversion of the prion protein.the cellular prion protein (prp(c)) is essential for the pathogenesis and transmission of prion diseases. prp(c) is bound to the plasma membrane via a glycosylphosphatidylinositol anchor, although a secreted, soluble form has also been identified. previously we reported that prp(c) is subject to ectodomain shedding from the membrane by zinc metalloproteinases with a similar inhibition profile to those involved in shedding the amyloid precursor protein. here we have used gain-of-function (overexp ...200919564338
nor98 scrapie identified in the united states.a distinct strain of scrapie identified in sheep of norway in 1998 has since been identified in numerous countries throughout europe. the disease is known as nor98 or nor98-like scrapie, among other names. distinctions between classic scrapie and nor98 scrapie are made based on histopathology and immunodiagnostic results. there are also differences in the epidemiology, typical signalment, and likelihood of clinical signs being observed. in addition, sheep that have genotypes associated with resi ...200919564493
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