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fatal neurological disease in scrapie-infected mice induced for experimental autoimmune encephalomyelitis.during the years or decades of prion disease incubation, at-risk individuals are certain to encounter diverse pathological insults, such as viral and bacterial infections, autoimmune diseases, or inflammatory processes. whether prion disease incubation time and clinical signs or otherwise the pathology of intercurrent diseases can be affected by the coinfection process is unknown. to investigate this possibility, mice infected with the scrapie agent at both high and low titers were subsequently ...200717626090
polymorphisms of the prnp gene in moroccan sheep breeds. 200717938411
modeling of a propagation mechanism of infectious prion protein; a hexamer as the minimum infectious unit.to construct a new model of the propagation mechanism of infectious scrapie-type prion protein (prp(sc)), here we conducted a disruption simulation of a prp(sc) nonamer using structure-based molecular dynamics simulation method based on a hypothetical prp(sc) model structure. the simulation results showed that the nonamer disrupted in cooperative manners into monomers via two significant intermediate states: (1) a nonamer with a partially unfolded surface trimer and (2) a hexamer and three monom ...200717678874
differential expression and protein distribution of bax in natural scrapie.bax is a pro-apoptotic member of the bcl-2 family that plays an important role in neuronal apoptosis. however, the results are controversial, especially regarding its function in the apoptosis involved in prion diseases. this work analyzes the gene expression and protein distribution of bax in the central nervous systems of sheep naturally infected with scrapie. gene expression profiling, obtained by means of real-time rt-pcr analysis, has shown a significant over-expression of this pro-apoptoti ...200717949698
differential expression of erythroid genes in prion disease.we previously reported reduced expression of erythroid-associated factor (eraf) within haematopoietic tissues of rodent scrapie models, suggesting an unrecognized role for the erythroid lineage in prion disease. in the present study, we compared the expression of a panel of erythroid genes within four murine scrapie models and five virus infection models with parallels to prion disease pathogenesis. we report that differential expression of erythroid genes is not limited to eraf, and is a common ...200717950692
classic scrapie in sheep with the arr/arr prion genotype in germany and france.in the past, natural scrapie and bovine spongiform encephalopathy (bse) infections have essentially not been diagnosed in sheep homozygous for the a136r154r171 haplotype of the prion protein. this genotype was therefore assumed to confer resistance to bse and classic scrapie under natural exposure conditions. hence, to exclude prions from the human food chain, massive breeding efforts have been undertaken in the european union to amplify this gene. we report the identification of 2 natural scrap ...200717953092
assessment of prion inactivation by fenton reaction using protein misfolding cyclic amplification and bioassay.an abnormal isoform of the prion protein, associated with transmissible spongiform encephalopathies, retains infectivity even after undergoing routine sterilization processes. we found that a formulation of iron ions combined with hydrogen peroxide effectively reduced infectivity and the level of abnormal isoforms of the prion protein in scrapie-infected brain homogenates. therefore, the fenton reaction has potential for prion decontamination.200717690456
direct detection of soil-bound prions.scrapie and chronic wasting disease are contagious prion diseases affecting sheep and cervids, respectively. studies have indicated that horizontal transmission is important in sustaining these epidemics, and that environmental contamination plays an important role in this. in the perspective of detecting prions in soil samples from the field by more direct methods than animal-based bioassays, we have developed a novel immuno-based approach that visualises in situ the major component (prp(sc)) o ...200717957252
[functions of prion protein prpc].it is now well established that both normal and pathological (or scrapie) isoforms of prion protein, prpc and prpsc respectively, are involved in the development and progression of various forms of neurodegenerative diseases, including scrapie in sheep, bovine spongiform encephalopathy (or "mad cow disease") and creutzfeldt-jakob disease in human, collectively known as prion diseases. the protein prpc is highly expressed in the central nervous system in neurons and glial cells, and also present ...200717875293
insights into prion strains and neurotoxicity.transmissible spongiform encephalopathies (tses) are neurodegenerative diseases that are caused by prions and affect humans and many animal species. it is now widely accepted that the infectious agent that causes tses is prp(sc), an aggregated moiety of the host-derived membrane glycolipoprotein prp(c). although prp(c) is encoded by the host genome, prions themselves encipher many phenotypic tse variants, known as prion strains. prion strains are tse isolates that, after inoculation into distinc ...200717585315
alteration of iron regulatory proteins (irp1 and irp2) and ferritin in the brains of scrapie-infected mice.considerable evidence suggests that oxidative stress may be involved in the pathogenesis of transmissible spongiform encephalopathies (tses). to investigate the involvement of iron metabolism in tses, we examined the expression levels of iron regulatory proteins (irps), ferritins, and binding activities of irps to iron-responsive element (ire) in scrapie-infected mice. we found that the irps-ire-binding activities and ferritins were increased in the astrocytes of hippocampus and cerebral cortex ...200717614197
oral scrapie infection modifies the homeostasis of peyer's patches' dendritic cells.in transmitted prion diseases the immune system supports the replication and the propagation of the pathogenic agent (prpsc). dcs, which are mobile cells present in large numbers within lymph organs, are suspected to carry prions through the lymphoid system and to transfer them towards the peripheral nervous system. in this study, c57bl/6 mice were orally inoculated with prpsc (scrapie strain 139a) and sacrificed at the preclinical stages of the disease. immunolabelled cryosections of peyer's pa ...200717622551
experimental scrapie in 'plt' mice: an assessment of the role of dendritic-cell migration in the pathogenesis of prion diseases.peripherally acquired transmissible spongiform encephalopathies display strikingly long incubation periods, during which increasing amounts of prions can be detected in lymphoid tissues. while precise sites of peripheral accumulation have been described, the mechanisms of prion transport from mucosa and skin to lymphoid and nervous tissues remain unknown. because of unique functional abilities, dendritic cells (dcs) have been suspected to participate in prion pathogenesis. in mice inoculated sub ...200717622642
is vaccination against transmissible spongiform encephalopathy feasible?prion diseases are a unique category of illness, affecting both animals and humans, where the underlying pathogenesis is related to a conformation change of the cellular form of a normal, self-protein called a prion protein (prp(c) [c for cellular]) to a pathological and infectious conformation known as scrapie form (prpsc [sc for scrapie]). currently, all prion diseases are without effective treatment and are universally fatal. the emergence of bovine spongiform encephalopathy and variant creut ...200717633306
investigations of a prion infectivity assay to evaluate methods of decontamination.prions are unique infectious agents which have been shown to be transmitted iatrogenically through contaminated surfaces. surface contamination is a concern on reusable medical devices and various industrial surfaces, but there is currently no standard, accepted model to evaluate surface prion decontamination. in this report, a set of both in vitro and in vivo methods were investigated based on the contamination of surface through artificial exposure to infected brain. an in vitro surface contam ...200717640752
prion strain- and species-dependent effects of antiprion molecules in primary neuronal cultures.transmissible spongiform encephalopathies (tse) arise as a consequence of infection of the central nervous system by prions and are incurable. to date, most antiprion compounds identified by in vitro screening failed to exhibit therapeutic activity in animals, thus calling for new assays that could more accurately predict their in vivo potency. primary nerve cell cultures are routinely used to assess neurotoxicity of chemical compounds. here, we report that prion strains from different species c ...200717913812
associations between genotypes at codon 171 and 136 of the prion protein gene and production traits in market lambs.to determine whether selection for the homozygous a136 r171 genotype that confers resistance to classic scrapie infection negatively affects production traits in sheep.200717916013
different structural stability and toxicity of prp(arr) and prp(arq) sheep prion protein variants.the polymorphisms at amino acid residues 136, 154, and 171 in ovine prion protein (prp) have been associated with different susceptibility to scrapie: animals expressing prp(arq) [prp(ala136/arg154/gln171)] show vulnerability, whereas those that express prp(arr) [prp(ala136/arg154/arg171)] are resistant to scrapie. the aim of this study was to evaluate the in vitro toxic effects of prp(arr) and prp(arq) variants in relation with their structural characteristics. we show that both peptides cause ...200717919292
ultrasensitive detection of scrapie prion protein using seeded conversion of recombinant prion protein.the scrapie prion protein isoform, prpsc, is a prion-associated marker that seeds the conformational conversion and polymerization of normal protease-sensitive prion protein (prp-sen). this seeding activity allows ultrasensitive detection of prpsc using cyclical sonicated amplification (pmca) reactions and brain homogenate as a source of prp-sen. here we describe a much faster seeded polymerization method (rprp-pmca) which detects >or=50 ag of hamster prpsc (approximately 0.003 lethal dose) with ...200717643109
hot spots in prion protein for pathogenic conversion.prion proteins are key molecules in transmissible spongiform encephalopathies (tses), but the precise mechanism of the conversion from the cellular form (prp(c)) to the scrapie form (prp(sc)) is still unknown. here we discovered a chemical chaperone to stabilize the prp(c) conformation and identified the hot spots to stop the pathogenic conversion. we conducted in silico screening to find compounds that fitted into a "pocket" created by residues undergoing the conformational rearrangements betwe ...200717616582
mechanistic insights into the cure of prion disease by novel antiprion compounds.prion diseases are fatal neurodegenerative disorders. identification of possible therapeutic tools is important in the search for a potential treatment for these diseases. congo red is an azo dye that has been used for many years to detect abnormal prion protein in the brains of diseased patients or animals. congo red has little therapeutic potential for the treatment of these diseases due to toxicity and poor permeation of the blood-brain barrier. we have prepared two congo red derivatives, des ...200717652397
distribution of prion protein genotypes in breeds of sheep in new zealand.to use an established high through-put genotyping procedure to gain an estimate of the frequency of alleles of the prion protein (prp) gene in some common sheep breeds in new zealand.200717928898
characterization of scrapie-infected and normal hamster blood as an experimental model for tse-infected human blood.ideally, the distribution and separation properties of blood-associated infectivity in humans infected with transmissible spongiform encephalopathies (tses) would be investigated using endogenously infected human blood. however, technical limitations prevent these studies. we report here an extensive comparison of component separations of tse-infected and normal hamster blood with normal human blood to evaluate its suitability as a model for tse-infected human blood. two leukotrap filtration sys ...200717486885
antiprion activity of cholesterol esterification modulators: a comparative study using ex vivo sheep fibroblasts and lymphocytes and mouse neuroblastoma cell lines.our studies on the role of cholesterol homeostasis in the pathogenesis of scrapie revealed abnormal accumulation of cholesterol esters in ex vivo peripheral blood mononuclear cells (pbmcs) and skin fibroblasts from healthy and scrapie-affected sheep carrying a scrapie-susceptible genotype compared to sheep with a resistant genotype. similar alterations were observed in mouse neuroblastoma n2a cell lines persistently infected with mouse-adapted 22l and rml strains of scrapie that showed up to thr ...200717709472
selective re-routing of prion protein to proteasomes and alteration of its vesicular secretion prevent prp(sc) formation.conversion of the cellular prion protein (prp(c)) into the abnormal scrapie isoform (prp(sc)) is the hallmark of prion diseases, which are fatal and transmissible neurodegenerative disorders. er-retained anti-prion recombinant single-chain fv fragments have been proved to be an effective tool for inhibition of prp(c) trafficking to the cell surface and antagonize prp(sc) formation and infectivity. in the present study, we have generated the secreted version of 8h4 intrabody (sec-8h4) in order to ...200717542810
experimental transmission of atypical scrapie to sheep.active surveillance for transmissible spongiform encephalopathies in small ruminants has been an eu regulatory requirement since 2002. a number of european countries have subsequently reported cases of atypical scrapie, similar to previously published cases from norway, which have pathological and molecular features distinct from classical scrapie. most cases have occurred singly in flocks, associated with genotypes considered to be more resistant to classical disease. experimental transmissibil ...200717725818
dendritic pathology in prion disease starts at the synaptic spine.spine loss represents a common hallmark of neurodegenerative diseases. however, little is known about the underlying mechanisms, especially the relationship between spine elimination and neuritic destruction. we imaged cortical dendrites throughout a neurodegenerative disease using scrapie in mice as a model. two-photon in vivo imaging over 2 months revealed a linear decrease of spine density. interestingly, only persistent spines (lifetime > or = 8 d) disappeared, whereas the density of transie ...200717553995
spiroplasma spp. from transmissible spongiform encephalopathy brains or ticks induce spongiform encephalopathy in ruminants.spiroplasma, small motile wall-less bacteria, are linked by molecular and serological studies to the transmissible spongiform encephalopathies (tses), which include scrapie in sheep, chronic wasting disease (cwd) in deer and creutzfeldt-jakob disease in humans. in this study, two experiments were undertaken to determine the role of spiroplasma in the pathogenesis of tse. in experiment 1, spiroplasma mirum, a rabbit tick isolate that had previously been shown to experimentally induce spongiform e ...200717761489
nonpsychoactive cannabidiol prevents prion accumulation and protects neurons against prion toxicity.prion diseases are transmissible neurodegenerative disorders characterized by the accumulation in the cns of the protease-resistant prion protein (prpres), a structurally misfolded isoform of its physiological counterpart prpsen. both neuropathogenesis and prion infectivity are related to prpres formation. here, we report that the nonpsychoactive cannabis constituent cannabidiol (cbd) inhibited prpres accumulation in both mouse and sheep scrapie-infected cells, whereas other structurally related ...200717804615
detection of the disease-associated isoform of the prion protein in formalin-fixed tissues by western blot.clinical signs of prion disease are not specific and include a variety of differential diagnoses. serological tests and nucleic acid-based detection methods are not applicable to prion-disease-agent detection because of the unusual nature of the infectious agent. prion-disease diagnosis is primarily conducted by means of immunodetection of the infectious agent, typically by at least 2 distinct procedures with immunohistochemistry and western blot being the most informative. these approaches diff ...200717823401
effectiveness of capillary electrophoresis fluoroimmunoassay of blood prpsc for evaluation of scrapie pathogenesis in sheep.management of prion diseases in livestock would benefit greatly from availability of a validated blood test. a promising immunocapillary electrophoresis technique (also known as capillary electrophoresis fluoroimmunoassay) to detect abnormal prion protein in blood from live sheep is evaluated here. capillary electrophoresis fluoroimmunoassay was applied to analysis of extracted blood from scrapie-exposed sheep (n = 87; 347 samples) at various stages of incubation, and to control sheep (n = 194; ...200717823402
role of galectin-3 in prion infections of the cns.galectin-3 is a multi-functional protein and participates in mediating inflammatory reactions. the pronounced overexpression of galectin-3 in prion-infected brain tissue prompted us to study the role of this protein in a murine prion model. immunofluorescence double-labelling identified microglia as the major cell type expressing galectin-3. ablation of galectin-3 did not affect prp(sc)-deposition and development of gliosis. however, galectin-3(-/-)-mice showed prolonged survival times upon intr ...200717555713
intraepithelial and interstitial deposition of pathological prion protein in kidneys of scrapie-affected sheep.prions have been documented in extra-neuronal and extra-lymphatic tissues of humans and various ruminants affected by transmissible spongiform encephalopathy (tse). the presence of prion infectivity detected in cervid and ovine blood tempted us to reason that kidney, the organ filtrating blood derived proteins, may accumulate disease associated prp(sc). we collected and screened kidneys of experimentally, naturally scrapie-affected and control sheep for renal deposition of prp(sc) from distinct, ...200717848990
assessing the involvement of migratory dendritic cells in the transfer of the scrapie agent from the immune to peripheral nervous systems.many transmissible spongiform encephalopathy (tse) agents accumulate upon follicular dendritic cells (fdcs) in lymphoid tissues before spreading to the brain. how tse agents spread from fdcs to the nervous system is not known as there is no physical fdc-nerve synapse. as fdcs form immobile networks we investigated whether other mobile cells might transfer tse agents between fdcs and peripheral nerves. we show that scrapie-infected mononuclear cells, b cells and migratory dendritic cells (dcs) we ...200717561271
modulation of proteinase k-resistant prion protein in cells and infectious brain homogenate by redox iron: implications for prion replication and disease pathogenesis.the principal infectious and pathogenic agent in all prion disorders is a beta-sheet-rich isoform of the cellular prion protein (prp(c)) termed prp-scrapie (prp(sc)). once initiated, prp(sc) is self-replicating and toxic to neuronal cells, but the underlying mechanisms remain unclear. in this report, we demonstrate that prp(c) binds iron and transforms to a prp(sc)-like form (*prp(sc)) when human neuroblastoma cells are exposed to an inorganic source of redox iron. the *prp(sc) thus generated is ...200717567949
cellular prion protein regulates beta-secretase cleavage of the alzheimer's amyloid precursor protein.proteolytic processing of the amyloid precursor protein (app) by beta-secretase, beta-site app cleaving enzyme (bace1), is the initial step in the production of the amyloid beta (abeta) peptide, which is involved in the pathogenesis of alzheimer's disease. the normal cellular function of the prion protein (prp(c)), the causative agent of the transmissible spongiform encephalopathies such as creutzfeldt-jakob disease in humans, remains enigmatic. because both app and prp(c) are subject to proteol ...200717573534
enteroglial and neuronal involvement without apparent neuron loss in ileal enteric nervous system plexuses from scrapie-affected sheep.the enteric nervous system (ens) probably plays a dominant role in sheep scrapie pathogenesis, but little is known about the cell types involved. we investigated the ileal myenteric and submucosal plexuses of four naturally and four orally experimentally scrapie-affected arq/arq sarda sheep, as well as those of 12 healthy-control sarda sheep carrying different prp genotypes. all scrapie-affected animals, euthanized at clinical-disease end stage, showed prpd deposition within enteric glial cells ...200717872545
scrapie in goats. 200717873273
exposure of sheep scrapie brain homogenate to rumen-simulating conditions does not result in a reduction of prp(sc) levels.experiments were designed to evaluate the potential of rumen-simulating conditions to reduce prp(sc) levels.200717576225
transcriptome analysis reveals altered cholesterol metabolism during the neurodegeneration in mouse scrapie model.to identify the dynamic transcriptional alterations in cns during the development of prion disease, brains of scrapie-infected mice and age-matched, mock-inoculated controls were analyzed immediately before inoculation and at different time points post-inoculation using affymetrix microarray technique. a total of 449 probe sets, representing 430 genes, showed differential expression between scrapie- and mock-inoculated mice over the time course. these genes could be separated into two clusters a ...200717437544
which prp haplotypes in a french sheep population are the most susceptible to atypical scrapie?a french sheep case control study has been organised to estimate the effects of the prp haplotypes on resistance to atypical scrapie. the alhq and afrq haplotypes are significantly more susceptible than the others.200717426916
mapping of possible prion protein self-interaction domains using peptide arrays.the common event in transmissible spongiform encephalopathies (tses) or prion diseases is the conversion of host-encoded protease sensitive cellular prion protein (prpc) into strain dependent isoforms of scrapie associated protease resistant isoform (prpsc) of prion protein (prp). these processes are determined by similarities as well as strain dependent variations in the prp structure. selective self-interaction between prp molecules is the most probable basis for initiation of these processes, ...200717430579
use of thermolysin in the diagnosis of prion diseases.the molecular diagnosis of prion diseases almost always involves the use of a protease to distinguish prpc from prpsc and invariably the protease of choice is proteinase k. here, we have applied the protease thermolysin to the diagnosis of animal prion diseases. this thermostable protease cleaves at the hydrophobic residues leu, ile, phe, val, ala, and met, residues that are absent from the protease accessible aminoterminal region of prpsc. therefore, although thermolysin readily digests prpc in ...200717435282
efficient in vitro amplification of a mouse-adapted scrapie prion protein.protein misfolding cyclic amplification (pmca) is a highly sensitive technique used to detect minute amounts of scrapie prion protein (prp(sc)), a major protein component of the infectious agents associated with prion diseases. although exponential in vitro amplification of hamster scrapie prp(sc) has been established, the pmca used was unsuccessful in achieving good amplification of prp(sc) from other animals. here, we have investigated the cause of the insufficient prp(sc) amplification in mic ...200717174030
diversity in neuroanatomical distribution of abnormal prion protein in atypical scrapie.scrapie is a transmissible spongiform encephalopathy (tse) in sheep and goats. in recent years, atypical scrapie cases were identified that differed from classical scrapie in the molecular characteristics of the disease-associated pathological prion protein (prp(sc)). in this study, we analyze the molecular and neuropathological phenotype of nine swiss tse cases in sheep and goats. one sheep was identified as classical scrapie, whereas six sheep, as well as two goats, were classified as atypical ...200717559305
a 12 000-rad whole-genome radiation hybrid panel in sheep: application to the study of the ovine chromosome 18 region containing a qtl for scrapie susceptibility.whole-genome radiation hybrid (rh) panels have been constructed for several species, including cattle. rh panels have proven to be an extremely powerful tool to construct high-density maps, which is an essential step in the identification of genes controlling important traits, and they can be used to establish high-resolution comparative maps. although bovine rh panels can be used with ovine markers to construct sheep rh maps based on bovine genome organization, only some (c. 50%) of the markers ...200717559555
scrapie: uncertainties, biology and molecular approaches.the study of the biology of scrapie in sheep is irretrievably associated with the genetics of the prp gene in sheep. control of susceptibility and resistance is so closely linked to certain alleles of the sheep prp gene that no review on scrapie can avoid prp genetics. before the importance of prp protein was discovered and before the influence of the gene itself on disease incidence was understood, it was clear there were some sheep which were more susceptible to natural scrapie than others and ...200717560089
cellular prion protein signaling in serotonergic neuronal cells.the cellular prion protein prp(c) is the normal counterpart of the scrapie prion protein prp(sc), the main component of the infectious agent of transmissible spongiform encephalopathies (tses). it is a ubiquitous cell-surface glycoprotein, abundantly expressed in neurons, which constitute the targets of tse pathogenesis. taking advantage of the 1c11 neuroectodermal cell line, endowed with the capacity to convert into 1c11(5-ht) serotonergic or 1c11(ne) noradrenergic neuronal cells, allowed us to ...200717405922
prevention of prion propagation by dehydrocholesterol reductase inhibitors in cultured cells and a therapeutic trial in mice.in prion diseases, the normal cellular form of prion protein (prp(c)) is converted into the disease-associated isoforms (prp(sc)) which accumulate in the infected tissues. although the precise mechanism of this conversion remains unsolved, drugs of various categories have been reported to reduce the accumulation of prp(sc) in prion-infected cultured cells. we here show that ay-9944 (a 7-dehydrocholesterol reductase inhibitor) and u18666a (a 24-dehydrocholesterol reductase inhibitor) prevent prp( ...200717409533
effects of post-translational modifications on prion protein aggregation and the propagation of scrapie-like characteristics in vitro.prion diseases, or transmissible spongiform encephalopathies (tses) are typically characterised by cns accumulation of prp(sc), an aberrant conformer of a normal cellular protein prp(c). it is thought prp(sc) is itself infectious and the causative agent of such diseases. to date, no chemical modifications of prp(sc), or a sub-population thereof, have been reported. in this study we have investigated whether chemical modification of amino acids within prp might cause this protein to exhibit aberr ...200717572162
could a virus contribute to weight gain?obesity is a serious public health problem associated with increased morbidity and mortality. although the causes for obesity are unclear, it seems that environmental, genetic, neural and endocrine factors contribute to its development. however, the rapid global spread of obesity resembles epidemiologically the spread of an infectious disease. thus far, little consideration has been given to the possibility that the epidemic of obesity could be due to an infectious agent. seven viruses and a scr ...200717420782
testing the equivalence of different ovine prp genotypes for estimated breeding values.in this study we applied equivalence testing methods to prove the absence of differences in genetic values of ewes with different prp genotypes. in particular, the milk production genetic value equivalence of arr ovine prion protein (prp) genotypes was analysed. there is no scientific evidence implying that the performances and genetic values of different prp genotypes will be different, but it is interesting to confirm that the performance of one genotype is indistinguishable from another befor ...200717651323
molecular profiling of ovine prion diseases by using thermolysin-resistant prpsc and endogenous c2 prp fragments.disease-associated prp fragments produced upon in vitro or in vivo proteolysis can provide significant insight into the causal strain of prion disease. here we describe a novel molecular strain typing assay that used thermolysin digestion of caudal medulla samples to produce prpres signatures on western blots that readily distinguished experimental sheep bovine spongiform encephalopathy (bse) from classical scrapie. furthermore, the accumulation of such prpres species within the cerebellum also ...200717652380
galectin-3 expression is correlated with abnormal prion protein accumulation in murine scrapie.to investigate the involvement of galectin-3 in the process of neurodegeneration in prion diseases, the expression and cellular localization of galectin-3 in the brain were studied in scrapie, a mouse model of prion disease. reverse transcription-polymerase chain reaction (rt-pcr) and western blot analyses showed that the expression of galectin-3 protein and mrna was induced in scrapie-affected brains, particularly at the time when the abnormal prion protein prp(sc) began to accumulate in the br ...200717531384
[development of molecular target based-therapy for prion diseases].prion diseases, or transmissible spongiform encephalopathies, are fatal, neurodegenerative diseases that include creutzfeldt-jacob disease (cjd) in humans, bovine spongiform encephalopathy (bse) and scrapie in animals. prion diseases are characterized by the accumulation of a misfolded prion protein, prpsc, which is made by a posttranslational conformational change of the host-encoded cellular prion protein, prpc. the process of the conformational change remains enigmatic, but a large number of ...200717447527
a novel real-time ultrasonic method for prion protein detection using plasminogen as a capture molecule.high resolution ultrasonography (hr-us) can monitor the molecular changes and biochemical interactions between proteins in real-time. the aim of this study was to use hr-us to characterize the real-time interactions between plasminogen coated beads and prpsc and to determine if this approach could be applied to the identification of animals affected by prion diseases. plasminogen, immobilized to beads, was used as a capturing tool for prpsc in brain homogenates from scrapie affected sheep and th ...200717659071
chronic wasting disease of deer and elk in transgenic mice: oral transmission and pathobiology.to study the pathogenesis of chronic wasting disease (cwd) in deer and elk, transgenic (tg) mice were generated that expressed the prion protein (prp) of deer containing a glycine at amino acid (aa) 96 and a serine at aa 225 under transcriptional control of the murine prp promoter. this construct was introduced into murine prp-deficient mice. as anticipated, neither non-tg mice nor prp ko mice were susceptible when inoculated intracerebrally (i.c.) or orally with cwd brain material (scrapie pool ...200717451773
copaxone interferes with the prp sc-gag interaction.the hallmark of prion disease-induced neurodegeneration is the accumulation of prp(sc), a misfolded form of prp(c). in addition, several lines of evidence indicate a role for the immune system and, in particular, inflammation in prion disease pathogenesis. in this work, we tested whether copaxone, an immunomodulatory agent currently used for the treatment of multiple sclerosis, can affect prion disease manifestation in scrapie-infected hamsters. we show here that copaxone exerted no effect on pr ...200717662008
treatment of scrapie pathogen 263k with tetracycline partially abolishes protease-resistant activity in vitro and reduces infectivity in vivo.to study the possible effect of tetracycline on protease-resistant activity in vitro and infectivity in vivo of a scrapie strain 263k.200717672209
infectivity of scrapie prion protein (prpsc) following in vitro digestion with bovine gastrointestinal microbiota.the influence of a complex microflora residing in the gastrointestinal tract of cattle on the prion protein plays a crucial role with respect to early pathogenesis and the potential infectivity of faeces resulting in contamination of the environment. it is unknown whether infectious prion proteins, considered to be very stable, are inactivated by microbial processes in the gastrointestinal tract of animals during digestion. in our previous study it was shown that the scrapie-associated prion pro ...200717542960
decrease in neuroinflammation after immunisation with synthetic prion peptides in an animal model of scrapie. 200717682891
analysis of multiple single nucleotide polymorphisms closely positioned in the ovine prnp gene using linear fluorescent probes and melting curve analysis.resistance and susceptibility to scrapie has been associated with single nucleotide polymorphisms located within codons 136, 154 and 171 of the ovine prion protein gene (prnp). dual-labelled hybeacon probes were developed to analyse single and clustered polymorphisms within these and neighbouring codons.200717683552
c1q binding and complement activation by prions and amyloids.c1q binds to many non-self and altered-self-materials. these include microorganisms, immune complexes, apoptotic and necrotic cells and their breakdown products, and amyloids. c1q binding to amyloid fibrils found as extracellular deposits in tissues, and subsequent complement activation are involved in the pathology of several amyloid diseases, such as alzheimer's disease. prion diseases, such as scrapie also involve formation of amyloid by polymerization of the host prion protein (prp). complem ...200717544820
[disease concept of the slow virus infection].this article gives a brief history of the terminology of slow virus infection, the conceptual change that occurred in it, the features common to slow infection and the current concept of slow virus infection. björn sigurdsson from the field of veterinary medicine proposed slow virus infection as unique mode of infection in 1954. its initial concept was remodeled along with the general acceptance of prion theory of sheep scrapie that was proposed in 1982. the features common to slow infection inc ...200717695269
[establishment of the concept of prion diseases].the history of prion diseases is derived from descriptions of scrapie of sheep and goats in the eighteenth century. in 1920, creutzfeldt-jakob disease was reported as the first case of human prion diseases, which was recognized as subacute spongiform encephalopathy, one of neurodegenerative diseases. afterwards, many transmission experiments were performed, which lead to the establishment of the fundamental concept, transmissible spongiform encephalopathy(tse). the infectious agent was supposed ...200717695271
disease dynamics over very different time-scales: foot-and-mouth disease and scrapie on the network of livestock movements in the uk.we analyse the relationship between the network of livestock movements in the uk and the dynamics of two diseases: foot-and-mouth disease (fmd), which has an incubation period of days, and scrapie, which incubates over years. for fmd, the time-scale of expected epidemics is similar to the time-scale of the evolution of the network. we argue that, under appropriate conditions, a static network analysis can be an appropriate tool for gaining insights into disease dynamics even when the relevant ti ...200717698478
cyclodextrins inhibit replication of scrapie prion protein in cell culture.prion diseases are fatal neurodegenerative disorders that are caused by the conversion of a normal host-encoded protein, prp(c), to an abnormal, disease-causing form, prp(sc). this paper reports that cyclodextrins have the ability to reduce the pathogenic isoform of the prion protein prp(sc) to undetectable levels in scrapie-infected neuroblastoma cells. beta-cyclodextrin removed prp(sc) from the cells at a concentration of 500 microm following 2 weeks of treatment. structure activity studies re ...200717699584
characterization of the properties and trafficking of an anchorless form of the prion protein.conversion of prp(c) into prp(sc) is the central event in the pathogenesis of transmissible prion diseases. although the molecular basis of this event and the intracellular compartment where it occurs are not yet understood, the association of prp with cellular membranes and in particular its presence in detergent-resistant microdomains appears to be of critical importance. in addition it appears that scrapie conversion requires membrane-bound glycosylphosphatidylinositol (gpi)-linked prp. the g ...200717556367
viruses as an etiology of obesity.obesity is a serious chronic disease that has numerous etiologies. the prevalence of obesity has increased dramatically since about 1980 in the united states and worldwide in both developed and developing countries. this rapid spread is compatible with an infectious origin. this review discusses the 5 animal viruses and 3 human viruses that have been shown to cause obesity and examines the evidence to date for virus-induced obesity. the obesogenic animal viruses include canine distemper virus, r ...200717908526
cellular prion protein (prpc) protects neuronal cells from the effect of huntingtin aggregation.the effect of normal cellular prion protein (prp(c)) on abnormal protein aggregation was examined by transfecting huntingtin fragments (htt) into sn56 neuronal-derived cells depleted of prp(c) by rna interference. prp(c) depletion caused an increase in both the number of cells containing granules and the number of apoptotic cells. consistent with the increase in htt aggregation, prp(c) depletion caused an decrease in proteasome activity and a decrease in the activities of cellular defense enzyme ...200717635996
hemin interactions and alterations of the subcellular localization of prion protein.hemin (iron protoporphyrin ix) is a crucial component of many physiological processes acting either as a prosthetic group or as an intracellular messenger. some unnatural, synthetic porphyrins have potent anti-scrapie activity and can interact with normal prion protein (prpc). these observations raised the possibility that hemin, as a natural porphyrin, is a physiological ligand for prpc. accordingly, we evaluated prpc interactions with hemin. when hemin (3-10 microm) was added to the medium of ...200717925394
prion protein alpha-to-beta transition monitored by time-resolved fourier transform infrared spectroscopy.the conformational change of the recombinant, murine prion protein (prp) from an alpha-helical to a beta-sheet enriched state was monitored by time-resolved fourier transform infrared (ft-ir) spectroscopy. the alpha-to-beta transition is induced by reduction of the single disulfide bond in prp. this transition is believed to generate the scrapie form prp(sc), the supposed infectious agent of transmissible spongiform encephalopathies. we followed the kinetics of this conformational change using a ...200717958950
frequencies of prp genotypes in meat breeds of japanese sheep and trail of selective breeding in experimental sheep flock.the selection of sheep with scrapie-resistant prp genotypes is one of the control measures for transmissible spongiform encephalopathies in ruminants. in this study, we investigated the frequencies of prp genotypes in meat breeds in japan. the nationwide surveillance revealed that nearly half of the suffolk sheep, a major meat breed in japan, carried scrapie-susceptible aq/aq and aq/vq genotypes. in addition, the vq haplotype, which confers high susceptibility to scrapie within sheep, was also f ...200718176036
[establishment of a protein misfolding cyclic amplification for prpsc].to establish a methodology of protein misfolding cyclic amplification (pmca) and utilize in the detection of prp(sc) in brain tissues from prion diseases.200717971920
[interaction between various prp segments and gfap in vitro].to study the potential interaction between prp protein and glial fibrillary acidic protein (gfap) and identify the binding region within prp with gfap.200717971924
relevance of the regional lymph node in scrapie pathogenesis after peripheral infection of hamsters.the exact role of the lymphoreticular system in the spread of peripheral prion infections to the central nervous system still needs further elucidation. against this background, the influence of the regional lymph node (ln. popliteus) on the pathogenesis of scrapie was monitored in a hamster model of prion infection via the footpad.200717894852
jak-stat signaling pathway mediates astrogliosis in brains of scrapie-infected mice.scrapie is characterized histologically, in part, by astrogliosis in brain and spinal cord. however, the mechanisms of astrogliosis in brain injury occurring during prion infection are not well understood. in this study, we investigated the expression levels and cellular localization of janus kinase (jak) -signal transducers and activators of transcription (stat) signaling molecules and growth factors such as leukemia inhibitory factor (lif) and ciliary neurotropic factor (cntf) by western blot ...200717897356
scrapie-specific pathology of sheep lymphoid tissues.transmissible spongiform encephalopathies (tses) or prion diseases often result in accumulation of disease-associated prp (prp(d)) in the lymphoreticular system (lrs), specifically in association with follicular dendritic cells (fdcs) and tingible body macrophages (tbms) of secondary follicles. we studied the effects of sheep scrapie on lymphoid tissue in tonsils and lymph nodes by light and electron microscopy. fdcs of sheep were grouped according to morphology as immature, mature or regressing ...200718074028
exposure assessment of tses from the landspreading of meat and bone meal.recent changes in european legislation have meant that certain processed abattoir waste, which has been appropriately heat treated and ground to a specified particle size, can be spread on nonpasture agricultural land. this has opened the way for the potential landspreading of mammalian meat and bone meal (mmbm) derived from animals slaughtered for human consumption. this article reports on two separate case studies (study 1 carried out in great britain (gb) and study 2 carried out in ireland) o ...200718076490
norwegian farmers' vigilance in reporting sheep showing scrapie-associated signs.scrapie is a chronic neurodegenerative disease affecting small ruminants and belongs to the transmissible spongiform encephalopathies. scrapie is considered a serious animal disease and it has been notifiable in norway since 1965. the clinical signs of scrapie might be vague and the farmers, if familiar with the signs of scrapie, are often in the best position for detecting scrapie suspects. in 2002, an anonymous questionnaire survey was conducted in order to assess norwegian sheep farmers' vigi ...200718076757
mutant prion protein d202n associated with familial prion disease is retained in the endoplasmic reticulum and forms 'curly' intracellular aggregates.transmissible spongiform encephalopathies are fatal neurodegenerative disorders of humans and animals that are familial, sporadic, and infectious in nature. familial disorders of humans include gerstmann-straussler-scheinker disease (gss), familial creutzfeldt-jakob disease (cjd), and fatal familial insomnia, and result from point mutations in the prion protein gene. although neurotoxicity in familial cases is believed to result from a spontaneous change in conformation of mutant prion protein ( ...200717873292
urinary excretion and blood level of prions in scrapie-infected hamsters.prions, infectious agents causing transmissible spongiform encephalopathy (tse), are composed primarily of the pathogenic form (prp(sc)) of the host-encoded prion protein. although very low levels of infectivity have been detected in urine from scrapie-infected rodents, no reports of urinary prp(sc) have been substantiated. studies on the dynamics of urinary prp(sc) during infection are needed to ensure the safety of urine-derived biopharmaceuticals and to assess the possible horizontal transmis ...200717872544
prions and prion diseases: fundamentals and mechanistic details.prion diseases, often called transmissible spongiform encephalopathies (tses), are infectious diseases that accompany neurological dysfunctions in many mammalian hosts. prion diseases include creutzfeldt-jakob disease (cjd) in humans, bovine spongiform encephalopathy (bse, "mad cow disease") in cattle, scrapie in sheep, and chronic wasting disease (cwd) in deer and elks. the cause of these fatal diseases is a proteinaceous pathogen termed prion that lacks functional nucleic acids. as demonstrate ...200718051314
predicting the consequences of selecting on prp genotypes on prp frequencies, performance and inbreeding in commercial meat sheep populations.selection programmes based on prion protein (prp) genotypes are being implemented for increasing resistance to scrapie. commercial meat sheep populations participating in sire-referencing schemes were simulated to investigate the effect of selection on prp genotypes on arr and vrq allele frequencies, inbreeding and genetic gain in a performance trait under selection. prp selection strategies modelled included selection against the vrq allele and in favour of the arr allele. assuming realistic in ...200718053577
interaction between dendritic cells and nerve fibres in lymphoid organs after oral scrapie exposure.in transmissible spongiform encephalopathies (tses), the infectious agent, called prpsc, an abnormal isoform of the cellular prion protein, accumulates and replicates in lymphoid organs before affecting the nervous system. to clarify the cellular requirements for the neuroinvasion of the scrapie agent from the lymphoid organs to the central nervous system, we have studied, by confocal microscopy, the innervations within peyer's patches, mesenteric lymph nodes and the spleen of mice in physiologi ...200717823814
cyclic tetrapyrrole sulfonation, metals, and oligomerization in antiprion activity.cyclic tetrapyrroles are among the most potent compounds with activity against transmissible spongiform encephalopathies (tses; or prion diseases). here the effects of differential sulfonation and metal binding to cyclic tetrapyrroles were investigated. their potencies in inhibiting disease-associated protease-resistant prion protein were compared in several types of tse-infected cell cultures. in addition, prophylactic antiscrapie activities were determined in scrapie-infected mice. the activit ...200717709470
polymorphisms of the prion gene promoter region that influence classical bovine spongiform encephalopathy susceptibility are not applicable to other transmissible spongiform encephalopathies in cattle.two regulatory region polymorphisms in the prion gene of cattle have been reported to have an association with resistance to classical bovine spongiform encephalopathy (bse). however, it is not known if this association also applies to other transmissible spongiform encephalopathies (tse) in cattle. in this report, we compare the relationship between these 2 polymorphisms and resistance in cattle affected with naturally occurring atypical bse as well as in cattle experimentally inoculated with e ...200717709775
prion protein expression differences in microglia and astroglia influence scrapie-induced neurodegeneration in the retina and brain of transgenic mice.activated microglia and astroglia are known to be involved in a variety of neurodegenerative diseases, including prion diseases. in the present experiments, we studied activation of astroglia and microglia after intraocular scrapie infection in transgenic mice expressing prion protein (prp) in multiple cell types (tg7 mice) or in neurons only (tgnse mice). in this model, scrapie infection and protease-resistant prp deposition occurs in the retinas of both strains of mice, but retinal degeneratio ...200717652390
mouse-adapted ovine scrapie prion strains are characterized by different conformers of prpsc.the agent responsible for prion disease may exist in different forms, commonly referred to as strains, with each carrying the specific information that determines its own distinct biological properties, such as incubation period and lesion profile. biological strain typing of ovine scrapie isolates by serial passage in conventional mice has shown some diversity in ovine prion strains. however, this biological diversity remains poorly supported by biochemical prion strain typing. the protein-only ...200717728226
the tyrosine kinase inhibitor imatinib mesylate delays prion neuroinvasion by inhibiting prion propagation in the periphery.prion diseases are fatal neurodegenerative disorders with no effective therapy. a hallmark of prion disease is the conversion of the normal cellular form of prion protein prp(c) into a disease-associated isoform prp(sc). the authors recently have shown that a tyrosine kinase inhibitor, imatinib mesylate, induces clearance of prp(sc) via specific inhibition of c-abl in prion-infected cell culture models. in this study, the authors assessed the in vivo effects of imatinib mesylate on prion disease ...200717849316
prion propagation in a nerve conduit model containing segments devoid of axons.prions, the putative causative agents of transmissible spongiform encephalopathies, are neurotropic pathogens that spread to the central nervous system via synaptically linked neural conduits upon peripheral infection. axons and their transport processes have been suggested as mediators of nerve-associated prion dissemination. however, the exact cellular components and molecular mechanisms underlying neural spread are unknown. this study used an established hamster scrapie model to pursue a nove ...200718024919
demographic risk factors for classical and atypical scrapie in great britain.following the bovine spongiform encephalopathy (bse) crisis, the european union has introduced policies for eradicating transmissible spongiform encephalopathies (tses), including scrapie, from large ruminants. however, recent european union surveillance has identified a novel prion disease, 'atypical' scrapie, substantially different from classical scrapie. it is unknown whether atypical scrapie is naturally transmissible or zoonotic, like bse. furthermore, cases have occurred in scrapie-resist ...200718024920
in vivo depletion of cd11c+ cells impairs scrapie agent neuroinvasion from the intestine.following oral exposure, some transmissible spongiform encephalopathy (tse) agents accumulate first upon follicular dendritic cells (dcs) in the galt. studies in mice have shown that tse agent accumulation in the galt, in particular the peyer's patches, is obligatory for the efficient transmission of disease to the brain. however, the mechanism through which tse agents are initially conveyed from the gut lumen to the galt is not known. studies have implicated migratory hemopoietic dcs in this pr ...200718025222
prion strain discrimination using luminescent conjugated polymers.the occurrence of multiple strains of prions may reflect conformational variability of prp(sc), a disease-associated, aggregated variant of the cellular prion protein, prp(c). here we used luminescent conjugated polymers (lcps), which emit conformation-dependent fluorescence spectra, for characterizing prion strains. lcp reactivity and emission spectra of brain sections discriminated among four immunohistochemically indistinguishable, serially mouse-passaged prion strains derived from sheep scra ...200718026110
the neurochemical nature of prp(c)-containing cells in the rat brain.the cellular prion protein (prp(c)) is a membrane-bound glycoprotein abundantly expressed in neurons and glial cells within the cns. the scrapie prion protein (prp(sc)) is a conformationally altered isoform of prp(c) that is responsible for prion diseases, also termed transmissible spongiform encephalopathies (tse), a group of neurodegenerative diseases that affect a wide variety of mammal species, including humans. the presence of the cellular isoform of prp is necessary for the establishment a ...200717854776
lambs with scrapie susceptible genotypes have higher postnatal survival.prion protein (prp) alleles associated with scrapie susceptibility persist in many sheep populations even with high frequencies despite centuries of selection against them. this suggests that scrapie susceptibility alleles have a pleiotropic effect or are associated with fitness or other traits that have been subject to selection.200718043743
cell division modulates prion accumulation in cultured cells.the phenotypic effect of prions on host cells is influenced by the physical properties of the prion strain and its level of accumulation. in mammalian cell cultures, prion accumulation is determined by the interplay between de novo prion formation, catabolism, cell division, and horizontal cell-to-cell transmission. understanding this dynamic enables the analytical modeling of protein-based heritability and infectivity. here, we quantitatively measured these competing effects in a subline of neu ...200717989223
assessment of prion inactivation by combined use of bacillus-derived protease and sds.prions, infectious agents causing transmissible spongiform encephalopathy, retain infectivity even after undergoing routine sterilization processes. we found that msk103 protease, identified in our previous study, effectively reduces infectivity and the level of misfolded isoform of the prion protein in scrapie-infected brain homogenates in the presence of sds. the treatment therefore can be applied to the decontamination of thermolabile instruments.200717928684
removal of the glycosylation of prion protein provokes apoptosis in sf126.although the function of cellular prion protein (prpc) and the pathogenesis of prion diseases have been widely described, the mechanisms are not fully clarified. in this study, increases of the portion of non-glycosylated prion protein deposited in the hamster brains infected with scrapie strain 263k were described. to elucidate the pathological role of glycosylation profile of prp, wild type human prp (huprp) and two genetic engineering generated non-glycosylated prp mutants (n181q/n197q and t1 ...200717927898
selective incorporation of polyanionic molecules into hamster prions.the central pathogenic event of prion disease is the conformational conversion of a host protein, prpc, into a pathogenic isoform, prpsc. we previously showed that the protein misfolding cyclic amplification (pmca) technique can be used to form infectious prion molecules de novo from purified native prpc molecules in an autocatalytic process requiring accessory polyanions (deleault, n. r., harris, b. t., rees, j. r., and supattapone, s. (2007) proc. natl. acad. sci. u. s. a. 104, 9741-9746). her ...200717940287
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