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alteration of b-cell subsets enhances neuroinvasion in mouse scrapie infection.acquired forms of prion diseases or transmissible spongiform encephalopathies are believed to occur following peripheral exposure. prions initially accumulate in the lymphoid system before spreading to the nervous system, but the underlying mechanisms for prion transfer between the two systems are still elusive. here we show that ablation of the b-cell-specific transmembrane protein cd19, a coreceptor of the complement system, results in an acceleration of prion neuroinvasion. this appears to be ...200818199638
structural and functional analysis of the ovine laminin receptor gene (rpsa): possible involvement of the lrp/lr protein in scrapie response.scrapie is a prion disease affecting sheep and goats. susceptibility to this neurodegenerative disease shows polygenic variance. the involvement of the laminin receptor (lrp/lr) in the metabolism and propagation of prions has previously been demonstrated. in the present work, the ovine laminin receptor gene (rpsa) was isolated, characterized, and mapped to ovine chromosome oar19q13. real-time rt-pcr revealed a significant decrease in rpsa mrna in cerebellum after scrapie infection. conversely, n ...200818202837
raman optical activity and circular dichroism reveal dramatic differences in the influence of divalent copper and manganese ions on prion protein folding.the binding of divalent copper ions to the full-length recombinant murine prion protein prp23-231 at neutral ph was studied using vibrational raman optical activity (roa) and ultraviolet circular dichroism (uv cd). the effect of the cu2+ ions on prp structure depends on whether they are added after refolding of the protein in water or are present during the refolding process. in the first case roa reveals that the hydrated alpha-helix is lost, with uv cd revealing a drop from approximately 25% t ...200818205409
experimental transmission of scrapie agent to susceptible sheep by intralingual or intracerebral inoculation.scrapie, a transmissible spongiform encephalopathy (tse), is a naturally occurring fatal neurodegenerative disease of sheep and goats. this study documents survival periods, pathological findings, and the presence of abnormal prion protein (prp(sc)) in genetically susceptible sheep inoculated with scrapie agent. suffolk lambs (aa/rr/qq at codons 136, 154, and 171, respectively) aged 4 mo were injected by the intralingual (il) or intracerebral (ic) route with an inoculum prepared from a pool of s ...200818214164
vaccine approaches to prevent and treat prion infection : progress and challenges.prion diseases are transmissible neurodegenerative diseases of humans and animals. the prion agent consists of a misfolded protein, prpsc (prion protein, scrapie form), of a glycosylphosphatidylinositol-anchored host protein, prpc (prp cellular form) of unknown function. during prion replication, prpsc induces host prpc to adopt its pathogenic conformation. some prpsc may aggregate to microscopically visible, extracellular prion plaques that stain for amyloid. the development of antiprion vaccin ...200818215090
genetic variability of the prnp gene in goat breeds from northern and southern italy.to determine the variability of the prion protein gene (prnp) in goats from northern and southern italy.200818217941
infection of metallothionein 1+2 knockout mice with rocky mountain laboratory scrapie.metallothioneins (mt) are heavy metal-binding, antioxidant proteins with relevant roles described in many pathological conditions affecting the central nervous system (cns). regarding prion diseases, a number of publications demonstrate an up-regulation of mt-1+2 in the brains of tse affected cattle, humans and experimentally inoculated rodents. since the prion protein also binds copper, and oxidative stress is one of the events presumably triggered by prpsc deposition, it seems plausible that m ...200818221736
new insights into early sequential prpsc accumulation in scrapie infected mouse brain evidenced by the use of streptomycin sulfate.to investigate the amplifying potentialities of streptomycin sulfate in the immunohistochemical (ihc) detection of the abnormal prion protein (prpsc), we used a sequential brain sampling from c506m3 scrapie strain inoculated c57bl/6 mice. the weekly removed brains, from 7 to 63 days post intra-cranial inoculation were analysed using prpsc ihc. the introduction of streptomycin sulfate, a technique developed for accurate cellular and regional mapping of prpsc deposition in several animal tses, rev ...200818224331
high incidence of subclinical infection of lymphoid tissues in scrapie-affected sheep flocks.prion diseases are characterized by a long incubation period. in scrapie, sheep may incubate and spread the infection for several years before clinical signs evolve. we have previously studied the occurrence of subclinical infection in the brain. now, we have studied the occurrence of subclinical infection in the brain and several lymphoid tissues in two scrapie-affected icelandic sheep flocks by immunohistochemistry for prp(sc), a molecular marker for infectivity, and correlated this with resul ...200818227967
intriguing nucleic-acid-binding features of mammalian prion protein.in transmissible spongiform encephalopathies, the infectious material consists chiefly of a protein, the scrapie prion protein prp(sc), that carries no genetic coding material; however, prions are likely to have accomplices that chaperone their activity and promote the conversion of the cellular prion protein prp(c) into the disease-causing isoform (prp(sc)). recent studies from several laboratories indicate that prp(c) recognizes many nucleic acids (nas) with high affinities, and we correlate t ...200818243708
copper(ii) ion binding to cellular prion protein.prion diseases are fatal neurodegenerative diseases thought to arise from the post-translational conversion of normal cellular prion protein to a scrapie isoform. experimental data suggest a role for copper(ii) ions in the process. an ab initio qm/mm approach and available experimental data were combined in order to identify and evaluate three potential copper(ii) ion binding sites in the c-terminal portion of the normal cellular prion protein. our results suggest that copper(ii) ion binds to hi ...200818247504
blood clearance of the prion protein introduced by intravenous route in sheep is influenced by host genetic and physiopathologic factors.the risk of transmissible spongiform encephalopathy (tse) transmission by blood transfusion is dependent on the blood concentrations of the pathologic isoform of prion protein (prpsc) but may also be influenced by blood concentrations of cellular prp (prpc). these concentrations are controlled by the blood clearance of prp, which has never been evaluated.200818248567
tse pathogenesis in cattle and sheep.many studies have been undertaken in rodents to study the pathogenesis of transmissible spongiform encephalopathies (tse). only a few studies have focused on the pathogenesis of bovine spongiform encephalopathy (bse) and scrapie in their natural hosts. in this review, we summarize the most recent insights into the pathogenesis of bse and scrapie starting from the initial uptake of tse agents and crossing of the gut epithelium. following replication in the gut-associated lymphoid tissues (galt), ...200818258167
progress and limits of prp gene selection policy.classical scrapie has proved to be a notoriously difficult disease to control due to a poor understanding of its natural history. the recognition of disease risk linkage to prp genotype has offered the prospect of a disease control strategy, viz. genotyping and selective breeding, novel to veterinary medicine when first considered in the 1990s. the uk spongiform encephalopathy advisory committee recommended the exploitation of this approach in a voluntary, national programme to control classical ...200818258168
the elusive intermediate on the folding pathway of the prion protein.a key molecular event in prion diseases is the conversion of the cellular conformation of the prion protein (prp(c)) to an altered disease-associated form, generally denoted as scrapie isoform (prp(sc)). the molecular details of this conformational transition are not fully understood, but it has been suggested that an intermediate on the folding pathway of prp(c) may be recruited to form prp(sc). in order to investigate the folding pathway of prp we designed and expressed two mutants, each posse ...200818279390
binding of 14-3-3 proteins to a single stranded oligodeoxynucleotide aptamer.a synthetic library of ca. 10(13) single stranded oligodeoxynucleotides, each comprising a randomized 40mer sequence and homogeneous 10mer flanking regions, was screened for binding to recombinant human 14-3-3gamma. a single aptamer, which showed similar affinities (k(d) approximately 10(-8)m) for six isoforms of the protein, has been shown to bind to undenatured 14-3-3 protein in the cerebral spinal fluid of scrapie infected sheep.200818279908
copper-induced structural changes in the ovine prion protein are influenced by a polymorphism at codon 112.prion diseases are associated with conformational change in the copper-binding protein prp. the copper-binding sites in prp are located in the n-terminal region of the molecule and comprise a series of tandem repeats of the sequence phgggwgq together with two histidines at residues 96 and 111 (human prp numbering). the co-ordination of copper ions within the non-octapeptide repeat metal ion-binding site involves met109 (human numbering, which corresponds with met112 in ovine prp) and the binding ...200818280261
the evidence of associations between prion protein genotype and production, reproduction, and health traits in sheep.the eu commission issued a regulation in 2003, which requires all member states to implement a breeding programme for resistance to transmissible spongiform encephalopathies in sheep by selecting for specific alleles of the prion protein (prp) gene. a key concern with regard to this regulation was that the intensive selection programmes, designed to increase resistance to scrapie, may have a negative impact on a range of other economically important production, reproduction, and disease traits i ...200818284907
prp genetics in ruminant transmissible spongiform encephalopathies.scrapie, bovine spongiform encephalopathy (bse), and chronic wasting disease (cwd) are prion diseases in ruminants with considerable impact on animal health and welfare. they can also pose a risk to human health and control is therefore an important issue. prion protein (prp) genetics may be used to control and eventually eradicate animal prion diseases. the prp gene in sheep and other representatives of the order artiodactyles has many polymorphisms of which several are crucial determinants of ...200818284908
approaches to investigating transmission of spongiform encephalopathies in domestic animals using bse as an example.bovine spongiform encephalopathy was a novel spongiform encephalopathy, in an hitherto unaffected species, that had characteristics of a point source epidemic, with an agent that could have been incorporated into a wide variety of feedstuffs and iatrogenically administered to naïve populations, and there was early evidence that it was not restricted to bovines. it was vital to establish, albeit experimentally, which other species might be affected, and whether the epidemic could be maintained by ...200818284911
sonication induced intermediate in prion protein conversion.we have observed that hamster prion protein (prp(c)) undergoes conformational changes on exposure to heat or sonication. if a sonication induced new conformer is seeded with a small amount of its abnormal pathogenic isoform (prp(sc)) it undergoes a significant conversion to a proteinase-resistant isoform. this suggests the presence of a third stable prp conformer, which may be intermediate in the conversion of prp(c) to prp(sc).200818289112
prp n-terminal domain triggers prp(sc)-like aggregation of dpl.transmissible spongiform encephalopathies are fatal neurodegenerative disorders thought to be transmitted by self-perpetuating conformational conversion of a neuronal membrane glycoprotein (prp(c), for "cellular prion protein") into an abnormal state (prp(sc), for "scrapie prion protein"). doppel (dpl) is a protein that shares significant biochemical and structural homology with prp(c). in contrast to its homologue prp(c), dpl is unable to participate in prion disease progression or to achieve a ...200817997980
the role of parvalbumin and calbindin d28k in experimental scrapie.prion diseases are generally characterized by pronounced neuronal loss. in particular, a subpopulation of inhibitory neurones, characterized by the expression of the calcium-binding protein parvalbumin (pv), is selectively destroyed early in the course of human and experimental prion diseases. by contrast, nerve cells expressing calbindin d28 k (cb), another calcium-binding protein, as well as pv/cb coexpressing purkinje cells, are well preserved.200818005331
gene expression profile of quinacrine-cured prion-infected mouse neuronal cells.prion diseases are transmissible fatal neurodegenerative diseases of humans and animals, characterised by the presence of an abnormal isoform (scrapie prion protein; prp(sc)) of the endogenous cellular prion protein (prp(c)). the pathological mechanisms at the basis of prion diseases remain elusive, although the accumulation of prp(sc) has been linked to neurodegeneration. different genomic approaches have been applied to carry out large-scale expression analysis in prion-infected brains and cel ...200818036195
prion proteins: physiological functions and role in neurological disorders.stanley prusiner was the first to promote the concept of misfolded proteins as a cause for neurological disease. it has since been shown by him and other investigators that the scrapie isoform of prion protein (prp(sc)) functions as an infectious agent in numerous human and non-human disorders of the central nervous system (cns). interestingly, other organ systems appear to be less affected, and do not appear to lead to major co-morbidities. the physiological function of the endogenous cellular ...200817707411
prion removal by nanofiltration under different experimental conditions.manufacturing processes used in the production of biopharmaceutical or biological products should be evaluated for their ability to remove potential contaminants, including tse agents. in the present study, we have evaluated scrapie prion protein (prp sc) removal in the presence of different starting materials, using virus removal filters of different pore sizes. following 75 nm filtration, prp sc was detected in the filtrate by western blot (wb) analysis when a "super-sonicated" microsomal frac ...200817890100
atypical status of bovine spongiform encephalopathy in poland: a molecular typing study.the aim of this study was to analyze molecular features of protease-resistant prion protein (prp(res)) in western blots of bse cases diagnosed in poland with respect to a possible atypical status. confirmed cases were analyzed by western blotting with several monoclonal antibodies directed at n-terminal and core epitopes of prion protein (prp). most cases showed the classical glycoprofile characterized by the dominance of the di- over the monoglycosylated prp(res) band, yielding di-/mono- ratios ...200817896076
protective effect of prion protein via the n-terminal region in mediating a protective effect on paraquat-induced oxidative injury in neuronal cells.transmissible spongiform encephalopathies are a group of neurodegenerative disorders caused by a posttranslational, conformational change in the cellular isoform of the prion protein (prp(c)) into an infectious, disease-associated form (prp(sc)). increasing evidence supports a role for prp(c) in the cellular response to oxidative stress. we investigated the effect of oxidative stress mediated by paraquat exposure on sh-sy5y neuroblastoma cells. a loss of mitochondrial membrane potential and subs ...200817896796
lack of prp(sc) immunostaining in intracranial ectopic lymphoid follicles in a sheep with concomitant non-suppurative encephalitis and nor98-like atypical scrapie: a case report.during active surveillance for transmissible spongiform encephalopathies (tses) in sheep, an initial reactor was detected using a rapid test on a brain sample. immunohistochemistry confirmed an atypical tse presentation that closely resembled the previously described nor98 cases. sequencing of the prnp gene confirmed the arq/ahq genotype with the l141f mutation at codon 141 associated with this phenotype. the head, including the brain and cranial lymphoid tissues, was sampled and examined thorou ...200817574883
single chain fv antibodies directed against the 37 kda/67 kda laminin receptor as therapeutic tools in prion diseases.transmissible spongiform encephalopathies are a group of neurological disorders associated with the deposition of prp(sc), an abnormal form of the cellular prion protein prp(c). the 37 kda/67 kda laminin receptor (lrp/lr) has been identified as a prion receptor and several lines of evidence strongly suggest that this protein plays a role during prion pathogenesis. here we report the selection of recombinant single chain antibodies (scfvs) directed against lrp from naïve and synthetic phage scfv ...200817576014
the importance of the prp genotype in active surveillance for ovine scrapie.surveillance activities for ovine scrapie have expanded in the 21st century, following concerns about the potential for a hidden epidemic of bovine spongiform encephalopathy in european sheep populations. large-scale surveys have been used to estimate the prevalence of scrapie infection. in this study we analyse data from the surveys in great britain between 2002 and 2004. when we estimate genotype-specific prevalences for each of the two screening tests used a difference is observed. one test u ...200817588284
analysis of prion protein genotypes in relation to reproduction traits in local and cosmopolitan german sheep breeds.due to the genetic determination of susceptibility to scrapie and other forms of transmissible spongiform encephalopathy (tse) in sheep breeding to the less susceptible prion protein (prp) genotype arr/arr was advanced within eu. in 4961 ewes of nine german sheep breeds (coburg fox sheep, gray horned heath sheep, merinoland sheep, rhoen sheep, german blackheaded mutton sheep, shropshire, suffolk, texel and white east friesian milk sheep) representing local and cosmopolitan breeds the reproductiv ...200817204379
[establishment of a prion disease prp(sc) panel from the brain tissues of experimental hamsters infected with scrapie agent 263k].to establish a prion disease prp(sc) panel from the brain tissues of experimental hamsters and to address the stability of the panel conserved under the specific condition, for evaluating the diagnostic techniques of human and animal's prion diseases.200819469162
the bank vole (myodes glareolus) as a sensitive bioassay for sheep scrapie.despite intensive studies on sheep scrapie, a number of questions remain unanswered, such as the natural mode of transmission and the amount of infectivity which accumulates in edible tissues at different stages of scrapie infection. studies using the mouse model proved to be useful for recognizing scrapie strain diversity, but the low sensitivity of mice to some natural scrapie isolates hampered further investigations. to investigate the sensitivity of bank voles (myodes glareolus) to scrapie, ...200819008382
histidine at codon 154 of the prion protein gene is a risk factor for nor98 scrapie in goats.prion protein gene (prnp) polymorphisms are involved in modulating the appearance of atypical/nor98 scrapie in sheep, with the alleles ahq and af141rq strongly associated with occurrence of the disease. the presence of histidine at codon 154 has also been detected in nor98-affected goats, but statistical analysis of the association between nor98 and goat prnp polymorphisms has not been reported previously. here, a case-control study was carried out on eight nor98-positive goats and 246 negative ...200819008408
in vitro amplification of prpsc derived from the brain and blood of sheep infected with scrapie.scrapie is a fatal, naturally transmissible, neurodegenerative prion disease that affects sheep and goats and is characterized by the accumulation of a misfolded protein, prpsc, converted from host-encoded prpc, in the central nervous system of affected animals. highly efficient in vitro conversion of host prpc to prpsc has been achieved in models of scrapie and in natural prion diseases by protein misfolding cyclic amplification (pmca). here, we demonstrate amplification, by serial pmca, of prp ...200819008409
prp antibody binding-induced epitope modulation evokes immunocooperativity.we have characterized the antibody-antigen binding events of the prion protein (prp) utilizing three new prp-specific monoclonal antibodies (mabs). the degree of immunoreactivity was dependent on the denaturation treatment with the combination of heat and sds resulting in the highest levels of epitope accessibility and antibody binding. interestingly however, this harsh denaturation treatment was not sufficient to completely and irreversibly abolish protein conformation. the mabs differed in the ...200818977037
a mirna signature of prion induced neurodegeneration.micrornas (mirnas) are small, non-coding rna molecules which are emerging as key regulators of numerous cellular processes. compelling evidence links mirnas to the control of neuronal development and differentiation, however, little is known about their role in neurodegeneration. we used microarrays and rt-pcr to profile mirna expression changes in the brains of mice infected with mouse-adapted scrapie. we determined 15 mirnas were de-regulated during the disease processes; mir-342-3p, mir-320, ...200818987751
a rapid accurate culture assay for infectivity in transmissible encephalopathies.the molecular and structural features of infectious agents that cause cjd, scrapie and bse remain controversial. a major impediment for agent resolution is the very long and expensive animal assays of infectivity. it is crucial to develop a rapid and broadly applicable cell culture assay to titer and compare different tse agent strains. because we found gt1 hypothalamic cells, unlike neuroblastoma n2a clones, were highly susceptible to a variety of tse agents, and could stably produce high agent ...200818989813
impact of strong selection for the prp major gene on genetic variability of four french sheep breeds(open access publication).effective selection on the prp gene has been implemented since october 2001 in all french sheep breeds. after four years, the arr "resistant" allele frequency increased by about 35% in young males. the aim of this study was to evaluate the impact of this strong selection on genetic variability. it is focussed on four french sheep breeds and based on the comparison of two groups of 94 animals within each breed: the first group of animals was born before the selection began, and the second, 3-4 ye ...200818990357
kuru likened to scrapie: the story remembered. 200818849258
frequency of prnp genotypes in common new zealand sheep breeds. 200818849578
reduction of prion infectivity in packed red blood cells.the link between a new variant form of creutzfeldt-jakob disease (vcjd) and the consumption of prion contaminated cattle meat as well as recent findings showing that vcjd can be transmitted by blood transfusion have raised public health concerns. currently, a reliable test to identify prions in blood samples is not available. the purpose of this study was to evaluate the possibility to remove scrapie prion protein (prp(sc)) and infectivity from red blood cell (rbc) suspensions by a simple washin ...200818851948
the early history of the transmissible spongiform encephalopathies exemplified by scrapie.transmissible spongiform encephalopathies (tse) is a group of diseases that is unique in comprising disorders that can occur sporadically, are hereditary and/or infectious. the transmissible pathogen--the prion--is distinct from all other pathogens in being devoid of nucleic acids. during the elucidation of these disorders, many different--and contradictory--theories have been put forward. early researchers, mostly driven by the economic impact of these diseases on sheep farming, engaged in heav ...200818951958
ablation of prion protein immunoreactivity by heating in saturated calcium hydroxide.prions, the infectious agents that cause transmissible spongiform encephalopathies (tses), are relatively resistant to destruction by physical, enzymatic, and chemical treatments. hydrolysis in boiling saturated calcium hydroxide (limewater) utilizes inexpensive chemicals to digest protein components of offal. the purpose of this work was to determine if incubating brain material from scrapie-infected sheep in near-boiling saturated calcium hydroxide solution (ca(oh)2) would abolish immunoreacti ...200818957103
accelerated prion replication in, but prolonged survival times of, prion-infected cxcr3-/- mice.prion diseases have a significant inflammatory component. glia activation, which is associated with increased production of cytokines and chemokines, may play an important role in disease development. among the chemokines upregulated highly and early upregulated during scrapie infections are ligands of cxcr3. to gain more insight into the role of cxcr3 in a prion model, cxcr3-deficient (cxcr3(-/-)) mice were infected intracerebrally with scrapie strain 139a and characterized in comparison to sim ...200818842729
green tea extracts interfere with the stress-protective activity of prp and the formation of prp.a hallmark in prion diseases is the conformational transition of the cellular prion protein (prp(c)) into a pathogenic conformation, designated scrapie prion protein (prp(sc)), which is the essential constituent of infectious prions. here, we show that epigallocatechin gallate (egcg) and gallocatechin gallate, the main polyphenols in green tea, induce the transition of mature prp(c) into a detergent-insoluble conformation distinct from prp(sc). the prp conformer induced by egcg was rapidly inter ...200818691383
effects of new amphotericin analogues on the scrapie isoform of the prion protein.prion diseases or transmissible spongiform encephalopathies (tses) are a group of neurodegenerative disorders associated with the conversion of a normal host prion protein (prp(c)) into a pathogenic isoform (prp(sc)). despite years of research, there is still no known cure for tses. amphotericin b (amb), an anti-fungal antibiotic, has antiprion activity but its usage is limited by its toxicity. this study assessed the antiprion properties of new amphotericin analogues in which the exocyclic carb ...200818691635
acute cellular uptake of abnormal prion protein is cell type and scrapie-strain independent.transmissible spongiform encephalopathies (tses) are fatal neurodegenerative diseases that include creutzfeldt-jakob disease, bovine spongiform encephalopathy and sheep scrapie. although one of the earliest events during tse infection is the cellular uptake of protease resistant prion protein (prp-res), this process is poorly understood due to the difficulty of clearly distinguishing input prp-res from either prp-res or protease-sensitive prp (prp-sen) made by the cell. using prp-res tagged with ...200818692214
prion gene (prnp) haplotype variation in united states goat breeds (open access publication).scrapie eradication efforts cost 18 million dollars annually in the united states and rely heavily upon prnp genotyping of sheep. genetic resistance might reduce goat scrapie and limit the risk of goats serving as a scrapie reservoir, so prnp coding sequences were examined from 446 goats of 10 breeds, 8 of which had not been previously examined at prnp. the 10 observed alleles were all related to one of two central haplotypes by a single amino acid substitution. at least five of these alleles (m ...200818694550
prion infected meat-and-bone meal is still infectious after biodiesel production.the epidemic of bovine spongiform encephalopathy (bse) has led to a world-wide drop in the market for beef by-products, such as meat-and-bone meal (mbm), a fat-containing but mainly proteinaceaous product traditionally used as an animal feed supplement. while normal rendering is insufficient, the production of biodiesel from mbm has been suggested to destroy infectivity from transmissible spongiform encephalopathies (tses). in addition to producing fuel, this method simultaneously generates a nu ...200818698417
increased oxidation, glycoxidation, and lipoxidation of brain proteins in prion disease.the basic molecular underpinnings of the pathological changes that unfold in prion disease remain elusive. a key role of increased oxidative stress has been hypothesized. given the transient nature of most intermediate molecules implicated, increased oxidative stress is better assessed by quantitating the damage it causes to macromolecules. we used mass spectrometry-based methods to measure specific products of protein oxidation, glycoxidation, and lipoxidation in brains from patients suffering ...200818703134
detection of infectious prions in urine.prions are the infectious agents responsible for prion diseases, which appear to be composed exclusively by the misfolded prion protein (prp(sc)). the mechanism of prion transmission is unknown. in this study, we attempted to detect prions in urine of experimentally infected animals. prp(sc) was detected in approximately 80% of the animals studied, whereas no false positives were observed among the control animals. semi-quantitative calculations suggest that prp(sc) concentration in urine is aro ...200818706416
accelerated prion disease pathogenesis in toll-like receptor 4 signaling-mutant mice.prion diseases such as scrapie involve the accumulation of disease-specific prion protein, prp(sc), in the brain. toll-like receptors (tlrs) are a family of proteins that recognize microbial constituents and are central players in host innate immune responses. the tlr9 agonist unmethylated cpg dna was shown to prolong the scrapie incubation period in mice, suggesting that innate immune activation interferes with prion disease progression. thus, it was predicted that ablation of tlr signaling wou ...200818715916
investigation of mcp1 as a quantitative trait gene for prion disease incubation time in mouse.the genetic basis of prion disease incubation time is principally determined by polymorphisms in the prion protein gene, prnp. however, it is now known that other genetic factors are important. several quantitative trait loci (qtl) have been identified across the genome including a broad region of linkage on mmu11. monocyte chemoattractant protein 1 (mcp-1) maps to this region and has been associated with microglial activation and reduced survival in the me7 mouse scrapie model of prion disease. ...200818716327
involvement of glypican-1 autoprocessing in scrapie infection.the copper-binding cellular prion protein (prp(c)) and the heparan sulphate (hs)-containing proteoglycan glypican-1 (gpc-1) can both be attached to lipid rafts via their glycosylphosphatidylinositol anchors, and copper ions stimulate their cointernalization from the cell surface to endosomes. the prion protein controls cointernalization and delivers copper necessary for s-nitrosylation of conserved cysteines in the gpc-1 core protein. later, during recycling through endosomal compartments, nitri ...200818717736
lactoferrin induces cell surface retention of prion protein and inhibits prion accumulation.prion diseases are fatal neurodegenerative disorders, and the conformational conversion of normal cellular prion protein (prp(c)) into its pathogenic, amyloidogenic isoform (prp(sc)) is the essential event in the pathogenesis of these diseases. lactoferrin (lf) is a cationic iron-binding glycoprotein belonging to the transferrin (tf) family, which accumulates in the amyloid deposits in the brain in neurodegenerative disorders, such as alzheimer's disease and pick's disease. in the present study, ...200818717818
creb-dependent gene regulation by prion protein: impact on mmp-9 and beta-dystroglycan.corruption of the normal function of the cellular prion protein (prp(c)) by the scrapie isoform (prp(sc)) emerges as a critical causal event in transmissible spongiform encaphalopathies (tse) pathogenesis. however, prp(c) physiological role remains unclear. by exploiting the properties of the 1c11 neuroectodermal cell line, able to convert into 1c11(5-ht) serotonergic or 1c11(ne) noradrenergic neuronal cells, we assigned a signaling function to prp(c). here, we establish that antibody-mediated p ...200818718863
lipids in the assembly of membrane proteins and organization of protein supercomplexes: implications for lipid-linked disorders.lipids play important roles in cellular dysfunction leading to disease. although a major role for phospholipids is in defining the membrane permeability barrier, phospholipids play a central role in a diverse range of cellular processes and therefore are important factors in cellular dysfunction and disease. this review is focused on the role of phospholipids in normal assembly and organization of the membrane proteins, multimeric protein complexes, and higher order supercomplexes. since lipids ...200818751913
excretion of transmissible spongiform encephalopathy infectivity in urine.the route of transmission of most naturally acquired transmissible spongiform encephalopathy (tse) infections remains speculative. to investigate urine as a potential source of tse exposure, we used a sensitive method for detection and quantitation of tse infectivity. pooled urine collected from 22 hamsters showing clinical signs of 263k scrapie contained 3.8 +/- 0.9 infectious doses/ml of infectivity. titration of homogenates of kidneys and urinary bladders from the same animals gave concentrat ...200818760007
molecular and transmission characteristics of primary-passaged ovine scrapie isolates in conventional and ovine prp transgenic mice.a more complete assessment of ovine prion strain diversity will be achieved by complementing biological strain typing in conventional and ovine prp transgenic mice with a biochemical analysis of the resultant prpsc. this will provide a correlation between ovine prion strain phenotype and the molecular nature of different prp conformers associated with particular prion strains. here, we have compared the molecular and transmission characteristics of ovine arq/arq and vrq/vrq scrapie isolates foll ...200818768980
a c-terminal protease-resistant prion fragment distinguishes ovine "ch1641-like" scrapie from bovine classical and l-type bse in ovine transgenic mice.the protease-resistant prion protein (prp(res)) of a few natural scrapie isolates identified in sheep, reminiscent of the experimental isolate ch1641 derived from a british natural scrapie case, showed partial molecular similarities to ovine bovine spongiform encephalopathy (bse). recent discovery of an atypical form of bse in cattle, l-type bse or base, suggests that also this form of bse might have been transmitted to sheep. we studied by western blot the molecular features of prp(res) in four ...200818769714
the effect of fenton reaction on protease-resistant prion protein (prpsc) degradation and scrapie infectivity.in prion diseases, metal imbalances in brain and/or metal substitutions for copper in prion protein suggest that metal-catalyzed oxidation (mco) and oxidative stress may affect cellular function and accumulation of protease-resistant prion protein (prp(sc)). we examined the effect of metal-induced oxidative stress by fenton reaction on prion protein with regard to its degradation, insolubility, and infectivity. precipitation and insolubility of prion protein were induced by fenton reaction in sc ...200818771660
[establishment of prp(sc) conversion based on serial pmca in vitro].in order to establish an amplification system in vitro with which the prp(sc) is able to convert prp(c) into proteinase k-resistant isoform infinitely and whether this system is more efficient than conventional protein misfolding cyclic amplification (pmca), scrapie strain 263k-infected hamster's brain homogenate and homologous normal brain homogenate were prepared, respectively. a new methodology, namely serial pmca, was utilized to reveal the continuous propagation ability of prp(sc). totally ...200818780631
prp genotype frequencies of quebec sheep breeds determined by real-time pcr and molecular beacons.the allele and genotype frequencies of the prion protein gene (prp), known to have an impact on scrapie susceptibility, were determined by real-time pcr for 500 quebec purebred rams. molecular beacons were very efficient in discriminating the 5 alleles investigated. polymorphisms at coding positions 136, 154, and 171 of the prp gene were analyzed using 3 separate real-time pcr reactions and a total of 7 molecular beacons. a total of 4 different alleles (arq, arr, ahr, and vrq) were observed at d ...200818783020
accumulation of citrullinated proteins by up-regulated peptidylarginine deiminase 2 in brains of scrapie-infected mice: a possible role in pathogenesis.peptidylarginine deiminases (pads), which are a group of posttranslational modification enzymes, are involved in protein citrullination (deimination) by the conversion of peptidylarginine to peptidylcitrulline in a calcium concentration-dependent manner. among the pads, pad2 is widely distributed in various tissues and is the only type that is expressed in brain. to elucidate the involvement of protein citrullination by pad2 in the pathogenesis of brain-specific prion diseases, we examined the p ...200818787103
quantitative recovery of scrapie agent with minimal protein from highly infectious cultures.there are few reports on the isolation, quantitative recovery, and relative purification of infectious particles that cause scrapie, creutzfeldt-jakob disease (cjd) and epidemic bovine spongiform encephalopathy (bse). because pure prion protein (prp) has failed to show significant infectivity, it is critical to find other molecules that are integral agent components. only complex diseased tissues such as degenerating brain have been fractionated, and agent recoveries have been quite low in conce ...200818788938
docosahexaenoic and eicosapentaenoic acids increase prion formation in neuronal cells.the transmissible spongiform encephalopathies, otherwise known as prion diseases, occur following the conversion of the cellular prion protein (prpc) to an alternatively folded, disease-associated isoform (prpsc). recent studies suggest that this conversion occurs via a cholesterol-sensitive process, as cholesterol synthesis inhibitors reduced the formation of prpsc and delayed the clinical phase of scrapie infection. since polyunsaturated fatty acids also reduced cellular cholesterol levels we ...200818789130
the effects of prion protein proteolysis and disaggregation on the strain properties of hamster scrapie.native mammalian prions exist in self-propagating strains that exhibit distinctive clinical, pathological and biochemical characteristics. prion strain diversity is associated with variations in prp(sc) conformation, but it remains unknown precisely which physical properties of the prp(sc) molecules are required to encipher mammalian prion strain phenotypes. in this study, we subjected prion-infected brain homogenates derived from three different hamster scrapie strains to either (i) proteinase ...200818796735
neuroanatomical distribution of abnormal prion protein in naturally occurring atypical scrapie cases in great britain.scrapie belongs to a group of diseases known as the transmissible spongiform encephalopathies or prion diseases. two different categories of naturally occurring scrapie have been identified: classical scrapie, which was first recorded around 1750, and atypical scrapie or 'nor-98', which was first identified in norway in 1998. the molecular characteristics of atypical scrapie have been well defined, but detailed descriptions of the neuropathological phenotype are rare since the majority of cases ...200818797889
environmentally-relevant forms of the prion protein.scrapie and chronic wasting disease (cwd) are prion diseases of particular environmental concern as they are horizontally transmissible and can remain infectious after years in the environment. recent evidence suggests that the n-terminus of prpsc, the infectious conformation of the prion protein, plays an important role in the mechanism of sorption to soil particles. we hypothesize that, in a prion-infected animal carcass, a portion of the n-terminus of prpsc could be cleaved by proteinases in ...200818800532
reduced translocation of nascent prion protein during er stress contributes to neurodegeneration.during acute stress in the endoplasmic reticulum (er), mammalian prion protein (prp) is temporarily prevented from translocation into the er and instead routed directly for cytosolic degradation. this "pre-emptive" quality control (pqc) system benefits cells by minimizing prp aggregation in the secretory pathway during er stress. however, the potential toxicity of cytosolic prp raised the possibility that persistent pqc of prp contributes to neurodegeneration in prion diseases. here, we find evi ...200818804434
assessing the presence of bse and scrapie in slaughterhouse wastewater.this paper describes a procedure for evaluating the presence and the stability of the proteinase k-resistant form of the prion protein (prp(res)) in slaughterhouse wastewater.200819146499
[from the mad cow to the scrapie of the european sheep]. 200819127901
a patient with mv2 subtype of sporadic creutzfeldt-jakob disease and atypical clinical presentation.we report the case of a 71-year-old woman with progressive dementia over the course of 4 years, characterized by prominent pyramidal signs and by the lack of ataxia and other cerebellar signs. creutzfeldt-jakob disease (cjd) was not suspected during the patient's life. autopsy brain tissue showed severe spongiform encephalopathy with kuru-like, but not florid, plaques in neocortex and cerebellum. massive synaptic diffuse and plaque-like prp(sc) deposition was found in the cerebral cortex, striat ...200819130739
[analyses of the expressions of gfap in the brain tissues of hamsters infected with various amounts of scrapie strain 263k at terminal stage].to investigate whether gliosis in the brain tissues of the hamsters infected with various amounts of scrapie strain 263k is correlated with the inoculation doses or the incubation times.200819105331
lions and prions and deer demise.contagious prion diseases--scrapie of sheep and chronic wasting disease of several species in the deer family--give rise to epidemics that seem capable of compromising host population viability. despite this prospect, the ecological consequences of prion disease epidemics in natural populations have received little consideration.200819107193
a bagging-based correction for the mixture model estimator of population size.estimation of a population size by means of capture-recapture techniques is an important problem occurring in many areas of life and social sciences. we consider the frequencies of frequencies situation, where a count variable is used to summarize how often a unit has been identified in the target population of interest. the distribution of this count variable is zero-truncated since zero identifications do not occur in the sample. as an application we consider the surveillance of scrapie in gre ...200819089886
prion interference with multiple prion isolates.co-inoculation of prion strains into the same host can result in interference, where replication of one strain hinders the ability of another strain to cause disease. the drowsy (dy) strain of hamster-adapted transmissible mink encephalopathy (tme) extends the incubation period or completely blocks the hyper (hy) strain of tme following intracerebral, intraperitoneal or sciatic nerve routes of inoculation. however, it is not known if the interfering effect of the dy tme agent is exclusive to the ...200819098442
epidemiological characteristics of classical scrapie outbreaks in 30 sheep flocks in the united kingdom.most previous analyses of scrapie outbreaks have focused on flocks run by research institutes, which may not reflect the field situation. within this study, we attempt to rectify this deficit by describing the epidemiological characteristics of 30 sheep flocks naturally-infected with classical scrapie, and by exploring possible underlying causes of variation in the characteristics between flocks, including flock-level prion protein (prp) genotype profile. in total, the study involved prp genotyp ...200819098982
prions in milk from ewes incubating natural scrapie.since prion infectivity had never been reported in milk, dairy products originating from transmissible spongiform encephalopathy (tse)-affected ruminant flocks currently enter unrestricted into the animal and human food chain. however, a recently published study brought the first evidence of the presence of prions in mammary secretions from scrapie-affected ewes. here we report the detection of consistent levels of infectivity in colostrum and milk from sheep incubating natural scrapie, several ...200819079578
prion propagation in vitro: are we there yet?prion diseases are caused by proteinaceous pathogens termed prions. although the details of the mechanism of prion propagation are not fully understood, conformational conversion of cellular prion protein (prp(c)) to misfolded, disease-associated scrapie prion protein (prp(sc)) is considered the essential biochemical event for prion replication. currently, studying prion replication in vitro is difficult due to the lack of a system which fully recapitulates the in vivo phenomenon. over the last ...200819015743
atypical prpsc distribution in goats naturally affected with scrapie.the brain and spinal cord of 48 goats from two greek herds in which scrapie had been reported were examined. all animals were symptomless at the time of euthanasia. notably, no lesions were observed either at the level of the obex or at other regions of the brain and spinal cord. immunohistochemical examination revealed prpsc labelling of the linear and fine punctuate types, mainly in the cerebral cortices, of 36 goats. twenty-seven of them were negative by elisa (designed to detect proteinase-r ...200818295782
overactivation of calcineurin induced by amyloid-beta and prion proteins.amyloid-beta protein (a beta) and the scrapie isoform of prion protein (prpss) have a central role in the pathogenesis of alzheimer's disease (ad) and prion-related encephalopathies (pre), respectively. in both disorders, the deposition of these misfolded proteins is accompanied by apoptotic neuronal loss. however, the pathogenesis and molecular basis of a beta- and prpsc-neurotoxic effects are not completely understood. the ca2+/calmodulin-dependent phosphatase calcineurin (can), through the de ...200818295934
antiprion properties of prion protein-derived cell-penetrating peptides.in prion diseases, the cellular prion protein (prp(c)) becomes misfolded into the pathogenic scrapie isoform (prp(sc)) responsible for prion infectivity. we show here that peptides derived from the prion protein n terminus have potent antiprion effects. these peptides are composed of a hydrophobic sequence followed by a basic segment. they are known to have cell-penetrating ability like regular cell-penetrating peptides (cpps), short peptides that can penetrate cellular membranes. healthy (gt1-1 ...200818296502
transmissible spongiform encephalopathies. 200819046027
urinary alpha1-antichymotrypsin: a biomarker of prion infection.the occurrence of blood-borne prion transmission incidents calls for identification of potential prion carriers. however, current methods for intravital diagnosis of prion disease rely on invasive tissue biopsies and are unsuitable for large-scale screening. sensitive biomarkers may help meeting this need. here we scanned the genome for transcripts elevated upon prion infection and encoding secreted proteins. we found that alpha(1)-antichymotrypsin (alpha(1)-act) was highly upregulated in brains ...200819057641
detection of prion infectivity in fat tissues of scrapie-infected mice.distribution of prion infectivity in organs and tissues is important in understanding prion disease pathogenesis and designing strategies to prevent prion infection in animals and humans. transmission of prion disease from cattle to humans resulted in banning human consumption of ruminant nervous system and certain other tissues. in the present study, we surveyed tissue distribution of prion infectivity in mice with prion disease. we show for the first time detection of infectivity in white and ...200819057664
prions in the environment: occurrence, fate and mitigation.scrapie and cwd are horizontally transmissible, and the environment likely serves as a stable reservoir of infectious prions, facilitating a sustained incidence of cwd in free-ranging cervid populations and complicating efforts to eliminate disease in captive herds. prions will enter the environment through mortalities and/or shedding from live hosts. unfortunately, a sensitive detection method to identify prion contamination in environmental samples has not yet been developed. an environmentall ...200819242120
pathologic prion protein infects cells by lipid-raft dependent macropinocytosis.transmissible spongiform encephalopathies, including variant-creutzfeldt-jakob disease (vcjd) in humans and bovine spongiform encephalopathies in cattle, are fatal neurodegenerative disorders characterized by protein misfolding of the host cellular prion protein (prp(c)) to the infectious scrapie form (prp(sc)). however, the mechanism that exogenous prp(sc) infects cells and where pathologic conversion of prp(c) to the prp(sc) form occurs remains uncertain. here we report that similar to the mec ...200819390657
infectious fold and amyloid propagation in podospora anserina.amyloid protein aggregation is involved in serious neurodegenerative disorders such as alzheimer's disease and transmissible encephalopathies. the concept of an infectious protein (prion) being the scrapie agent was successfully validated for several yeast and fungi proteins. ure2, sup35 and rnq1 in saccharomyces cerevisiae and het-s in podospora anserina have been genetically and biochemically identified as prion proteins. studies on these proteins have revealed critical information on the mech ...200719164904
yeast prions: evolution of the prion concept.prions (infectious proteins) analogous to the scrapie agent have been identified in saccharomyces cerevisiae and podospora anserina based on their special genetic characteristics. each is a protein acting as a gene, much like nucleic acids have been shown to act as enzymes. the [ure3], [psi(+)], [pin(+)] and [het-s] prions are self-propagating amyloids of ure2p, sup35p, rnq1p and the het-s protein, respectively. the [beta] and [c] prions are enzymes whose precursor activation requires their own ...200719164928
anti-lrp/lr antibody w3 hampers peripheral prpsc propagation in scrapie infected mice.we identified the 37kda/67kda laminin receptor (lrp/lr) as a cell surface receptor for the cellular prion protein (prp(c)) and the infectious prion protein (prp(sc)). recently, we showed that anti-lrp/lr antibody w3 cured scrapie infected n2a cells. here, we demonstrate that w3 delivered by passive immunotransfer into c57bl/6 mice reduced the prp(sc) content in the spleen significantly by 66%, demonstrating an impairment of the peripheral prp(sc) propagation. in addition, we observed a 1.8-fold ...200719164931
the evolution of internet-based map server applications in the united states department of agriculture, veterinary services.the internet is used increasingly as an effective means of disseminating information. for the past five years, the united states department of agriculture (usda) veterinary services (vs) has published animal health information in internet-based map server applications, each oriented to a specific surveillance or outbreak response need. using internet-based technology allows users to create dynamic, customised maps and perform basic spatial analysis without the need to buy or learn desktop geogra ...200720422551
is there a relationship between prion protein genotype and ovulation rate and litter size in sheep?the identification of an association between polymorphisms of the prion protein (prp) gene and susceptibility to scrapie has enabled the development of breeding programmes to increase natural resistance to scrapie. it is, however, imperative to identify if such selection would affect important reproduction and production traits. the objective of this study was to determine if there is a relationship between polymorphisms at codons 136, 154 and 171 of the prp gene and ovulation rate or litter siz ...200717204381
nitric oxide synthase immunoreactivity and nadph-d histochemistry in the enteric nervous system of sarda breed sheep with different prp genotypes in whole-mount and cryostat preparations.until now, significant differences in the neurochemical pattern of enteric neurons have been demonstrated in all species studied; however, some strong similarities also occur across species, such as the occurrence of nitric oxide synthase immunoreactivity (nos-ir) in inhibitory motor neurons to muscle. in consideration of the insufficient data regarding the enteric nervous system (ens) of sheep, we investigated the myenteric plexus and submucosal plexus of the ovine ileum. since the pivotal role ...200717210925
diagnosing scrapie in sheep: a classification experiment.scrapie is a neuro-degenerative disease in small ruminants. a data set of 3113 records of sheep reported to the scrapie notifications database in great britain has been studied. clinical signs were recorded as present/absent in each animal by veterinary officials (vo) and a post-mortem diagnosis was made. in an attempt to detect healthy animals within the set of suspects using only the clinical signs, 18 classification methods were applied ranging from simple linear classifiers to classifier ens ...200717222398
[the early history of transmissible spongiform encephalopathies exemplified by scrapie].transmissible spongiform encephalopathies (tse) are unique diseases in that they are sporadic, hereditary, and infectious. the transmissible pathogen--the prion--stands out from all other pathogens in being devoid of nucleic acids. instead its most important and possibly only constituent is a host-encoded protein, the prion protein (prp), in an alternative conformation induced by post-translational modifications. thus tses belong to and are so far the only transmissible member of the continuousl ...200717226012
characterization of a proteolytic enzyme derived from a bacillus strain that effectively degrades prion protein.the purpose of this paper was to screen candidate bacterial strains for the production of proteases suitable for application to the degradation of pathogenic forms of prion protein (prp(sc)). this paper describes the biochemical characteristics and proteolytic activity of the isolated protease.200717241357
il-1 family members as candidate genes modulating scrapie susceptibility in sheep: localization, partial characterization, and expression.scrapie (sc) is a transmissible spongiform encephalopathy (tse) in sheep and goats. susceptibility to this neurodegenerative disease is controlled mainly by point mutations at the prnp locus. other genes, apart from prnp, have been reported to modulate resistance/susceptibility to sc. on the basis of several studies on alzheimer's disease and different tse models, and of requirement for correct homeostasis of cytokines in brain, il1b and il1rn were chosen as putative positional and functional ca ...200717242860
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