Variably Protease-Sensitive Prionopathy, Prionpathy, Prionopathy, FFI, GSS, gCJD, hvCJD, sCJD, TSE, PRION, update 2011
Bio.130: Comparison of Sheep Nor98 with Human Variably Protease-Sensitive Prionopathy and Gerstmann-Sträussler-Scheinker Disease
Laura Pirisinu,1,? Romolo Nonno,1 Pierluigi Gambetti,2 Umberto Agrimi1 and Wen-Quan Zou2
1Istituto Superiore di Sanita; Rome, Italy; 2Case Western Reserve University; Cleveland, OH USA;?Presenting author; Email: laura.pirisinu@iss.it
Background. Nor98 is an atypical scrapie characterized by the presence of a small N- and C-terminally truncated fragment of the prion protein which has the electrophoretic mobility of ~8 kDa and is highly resistant to proteinase K (PK) (PrPres). A similar internal PrPres fragment has also been observed in human prion diseases including Gerstmann-Sträussler-Scheinker disease (GSS) and Variably Protease-Sensitive Prionopathy (VPSPr).
In view of these molecular analogies and the implications concerning strain similarity between animal and human TSEs, we compared the physico-chemical properties of the Nor98 ~8 kDa PrPres fragment with those associated with the two human prion diseases, in order to investigate the extent of the similarity between animal and human prion strains.
Methods. Brain tissues from Nor98 isolates with different genotypes (n = 7), VPSPr cases with 129VV, 129MV, 129MM genotypes (n = 6) and GSS cases with A117V, F198S and P102L mutations (n = 8) were analyzed by western blotting in the following studies: (1) investigating N- and C-terminal PK cleavage sites of PrPres by epitope mapping; (2) comparing conformational stability and detergent-solubility of PrPSc by CSSA (conformational stability and solubility assay).
Results and Conclusions. Comparative analysis of the electrophoretic mobilities revealed that the relative molecular weight of the Nor98 PrPres internal fragment is greater than those of the matching fragment associated with VPSPr and GSSA117V, whereas it is similar to those of GSSF198S and GSSP102L. However, epitope mapping suggests that the PrPres internal fragments have different N- and C- terminal cleavage sites in each disease. Finally, preliminary results by CSSA indicate that the PrP conformational stability of human and sheep TSEs characterized by internal PrPres fragments is also different, with VPSPr showing a higher conformational stability than Nor98. Overall, our results show an unexpected heterogeneity of the molecular features among human and sheep TSEs associated with internal PrPres fragments, which is consistent with strain diversity despite the presence of similar PrPres fragments.
Supported by the Italian Ministry of Health, the National Institutes of Health (NIH) NS062787, NIH AG-08012, AG-14359, Alliance BioSecure, as well as CDC Contract UR8/CCU515004.
http://www.prion2011.ca/files/PRION_2011_-_Posters_(May_5-11).pdf
SEE FULL TEXT ;
Monday, June 27, 2011
Comparison of Sheep Nor98 with Human Variably Protease-Sensitive Prionopathy and Gerstmann-Sträussler-Scheinker Disease
http://prionopathy.blogspot.com/2011/06/comparison-of-sheep-nor98-with-human.html
S2-3: Variably Protease-sensitive Prionopathy: Update on this Novel Human Prion Disease
Pierluigi Gambetti
National Prion disease Pathology Surveillance Center; Institute of Pathology; Case Western Reserve University; Cleveland, OH USA
Key words: VPSPr, protease-sensitive, ladder-like, prionopathy, tau, novel prion disease
Introduction. Initially we described a novel prion disease affecting subjects valine homozygous at codon 129 (129VV) of the prion protein (PrP) gene and associated with an abnormal PrP (PrPDis) that was largely protease-sensitive. We recently reported that an overall similar disease also affects subjects that are 129 methionine/valine heterozygous (129MV) and methionine homozygous (129MM) although clinical histopathological and PrPDis features are distinguishable in the three 129 genotypes. Specifically, although the three PrPDis show the same electrophoretic pattern, they have different degrees of protease resistance and PrP antibody immunoreactivities. None of the VPSPr cases reported to date carries a mutation in the PrP gene open reading frame.
Results. We will report data from the three VPSPr genotypes related to (1) presence of tau and Aflpathology; (2) CSI features; (3) PMCA data on the propensity of PrPDis to act as template and convert PrPC to a similar PrPDis isoform; (4) further comparative analysis with Gerstmann-Sträussler-Scheinker disease (GSS).
Discussion. We will focus on the nature and classification of VPSPr when compared to classic and atypical prion diseases such CJD and GSS, respectively, as well as to other neurodegenerative diseases such as the tauopathies which have been shown to propagate in receptive animals.
Patients and Methods. We have carried out comparative clinical, histopathological and immunohistochemical examinations as well as PrPDis analyses in 29 cases received from the US and Italy (Drs. F. Tagliavini and P. Parchi). Conformation stability assay (CSI) and protein misfolding cyclic amplification (PMCA) were carried out in several of these cases.
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Oral.34: Variably Protease-Sensitive Prionopathy: Transmissibility and PMCA Studies
Pierluigi Gambetti,1,† Wenquan Zou,1 Juan Maria Torres,2 Claudio Soto,3 Silvio Notari,2 Juan Carlos Espinosa2 and Xiangzhu Xiao1
1 Case Western Reserve University; Cleveland, OH USA; 2 Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria; Madrid, Spain; 3 Mitchell Center for Alzheimer Disease and Related Brain Disorders, University of Texas; Houston, TX USA†Presenting author; Email: pxg13@case.edu
Variably protease-sensitive prionopathy (VPSPr) is an atypical, apparently sporadic prion disease affects all three genotypes—VV, MV and MM—at codon 129 of the prion protein (PrP) gene. A distinctive and common feature of VPSPr three genotypes is the presence of abnormal PrP forming a ladder-like electrophoretic pattern with variable sensitivity to protease digestion according to the 129 genotype. These atypical features have raised the issue of VPSPr transmissibility to animals and its propensity of being replicated in vitro.
We now report the initial results of an extensive study on the capacity of the VPSPr-associated abnormal PrP to propagate by bioassay and by protein misfolding cyclic amplification (PMCA). Inoculation of brain homogenates from cases of VPSPr-129VV to transgenic (Tg) mice expressing human PrP-129V at 6X normal revealed no clinical phenotype during the normal life span of the inoculated mice. Peculiar PrP plaques with a distinctive topography were present in approximately 30% of the mice with minimal or no spongiform degeneration (SD). Abnormal PrP from several of the plaque-bearing mice displayed a ladder-like electrophoretic profile similar to that of VPSPr. In contrast, Tg mice inoculated with brain homogenate from sporadic CJD-129VV associated with scrapie PrP type 2 became symptomatic and died approximately 220 days post inoculation. They showed widespread SD with only occasional, differently distributed plaques and a typical 3-band or PrP27-30 electrophoretic profile of the protease resistant PrP. Sham- or not inoculated mice revealed no pathology and no ladder or PrP27-30 profiles. The ladder-like electrophoretic profile was also obtained from VPSPr-129VV under modified PMCA conditions. Second passage experiments are underway.
These results support the notion that VPSPr is a prion condition different from classical prion diseases and more like other conformational neurodegenerative diseases such as Alzheimer disease and tauopathies.
Note
Supported by NIH NS062787, AG-08012, AG-14359, CDC UR8/CCU515004 and the Britton Fund.
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Bio.183: Association Between a Familial and a Newly-Identified Prion Disease
Xiangzhu Xiao,1 Jue Yuan,1 Ignazio Cali,1 Xiaochen Zhou,1 Jeanne Grosclaude,2 Hubert Laude,2 Robert B. Petersen,1 Pierluigi Gambetti1 and Wenquan Zou1,†
1Case Western Reserve University; Cleveland, OH USA; 2Virologie Immunologie Moléculaires; Jouy-en-Josas, France†Presenting author; Email: wenquan.zou@case.edu
Variably protease-sensitive prionopathy (VPSPr) is a newly-identified sporadic prion disease characterized not only by an atypical clinical phenotype and neuropathology, but also by the deposition in the brain of a peculiar prion (PrPSc). The molecular mechanism underlying the formation of the peculiar PrPSc remains unknown. A naturally-occurring pathogenic mutation, valine (V) to isoleucine (I), at PrP residue 180 is linked to familial Creutzfeldt-Jakob disease (fCJDV180I). Here we report that the prions formed in VPSPr and fCJDV180I exhibit striking similarities in glycosylation, enzymatic fragmentation, and immunoreactivity even though they are associated with either wild-type PrP (PrPWt) or mutated PrP, respectively. First, we demonstrate that lack of the proteinase K (PK)-resistant diglycosylated PrP species (PrPDigly) observed in both fCJDV180I and VPSPr results from loss of glycosylation at the first N-linked glycosylation site. Second, although lack of PrPDigly has also been reported in fCJD linked to the PrP Thr183Ala mutation (fCJDT183A, which abolishes the first glycosylation site) and an atypical CJD case, so far fCJDV180I is the only one that is of the peculiar PrPSc with the five-step ladder-like electrophoretic profile (LLEP), a pathognomonic molecular hallmark of VPSPr. Third, PrP with LLEP from the two diseases is preferentially detected by the anti-PrP antibody 1E4, but not by 3F4 although these PrP fragments contain both epitopes. Fourth, unlike fCJDT183A, both VPSPr and fCJDV180I show lack of PrPDigly only in PK-treated but not in untreated PrP. Finally, PrPDigly was detected in PrPWt and PrPV180I, but not in PrPT183A, in cell models. Our study suggests that fCJDV180I shares similar pathogenetic mechanism(s) with VPSPr and that cells and animals expressing human PrPV180I can be used as models for investigating the molecular mechanism underlying the formation of the peculiar PrPSc.
Supported by the National Institutes of Health (NIH) NS062787, NIH AG-08012, AG-14359, the CJD Foundation, Alliance BioSecure, the University Center on Aging and Health with the support of the McGregor Foundation and the President’s Discretionary Fund (CWRU) as well as CDC Contract UR8/CCU515004.
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Bio.135: Characterization of the Agent Strain in Sporadic Creutzfeldt-Jakob Disease by Transmission to Wild-Type Mice
Diane L. Ritchie,1,† Aileen Boyle,2 Irene McConnell,2 Mark W. Head,1 James W. Ironside1 and Moira E. Bruce2
1National CJD Surveillance Unit; Edinburgh, UK; 2Neuropathogenesis Division, The Roslin Institute and Royal (Dick) School of Veterinary Studies, The Roslin Institute, Roslin Biocentre; Roslin, UK†Presenting author; Email: diane.ritchie@ed.ac.uk
Transmissible spongiform encephalopathy (TSE) strains are defined by their biological properties on transmission to wild-type (wt) mice, specifically by their characteristic incubation periods and patterns of vacuolar pathology ("lesion profiles") in the brain. While a single TSE strain has been identified in variant Creutzfeldt-Jakob disease (vCJD), the phenotypic heterogeneity observed in sporadic CJD (sCJD) implies the existence of multiple strains of agent. These distinct strains are proposed to be enciphered by the different conformers of abnormal prion protein (PrP), recognized as different protease resistant PrP (PrPres) types by western blotting (type 1 or type 2) and are thought to be substantially influenced by the prion protein gene (PRNP) codon 129 (M/V) polymorphism.
To test the relationship between disease phenotype and agent strain, we investigated the transmission characteristics of the TSE agents present in brain tissue from 27 sCJD cases (comprising all six possible combinations of PRNP codon 129 genotype and PrPres type) in panels of wt mice using the standard strain typing properties of incubation period and lesion profiles, plus a full analysis of PrP present in the mouse brain. The work was extended to include analysis of subsequent mouse-to-mouse passages.
The results demonstrated the existence of at least two strains of agent, one associated with the MM1/MV1 sCJD subgroup and the other associated with the MM2 subgroup. The lack of transmission in mice challenged with tissues from VV1, MV2 and VV2 sCJD subgroups provided evidence of at least one further sCJD strain. Overall, the PrPres type in sCJD was maintained on transmission, which is consistent with the proposition that PrPres type plays a role in enciphering strain-specific information.
This study highlights a complex relationship between disease phenotype, codon 129 PRNP genotype, PrPres type and agent strain in sCJD and confirms that multiple strains of agent are associated with sCJD, some of which successfully propagate in wt mice. The sCJD strains identified here, by their biological properties partially correlates with the current sub-classification system for sCJD, which is based on the clinical and pathological phenotype of the disease.
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Bio.144: Analyses of PrPSc Aggregation State and Protease-Resistance in Human Prions
Daniela Saverioni,1,† Silvio Notari,2 Sabina Capellari1 and Piero Parchi1
1Department of Neurological Sciences, University of Bologna; Bologna, Italy; 2Department of Pathology, National Prion Disease Pathology Surveillance Center, Case Western Reserve University; Cleveland, OH USA†Presenting author; Email: daniela.saverioni@studio.unibo.it
Background. Given the complexity and costs of transmission studies, the analyses of PrPSc properties is increasingly used as surrogate marker for strain typing. Early studies showed that PrPSc extracted from distinct disease phenotypes, in both animals and humans, often differ in physicochemical properties, such as fragment size after protease treatment or glycoform ratio. More recently, studies mainly conducted with scrapie strains isolated in mice or hamster have also reported strain-specific PrPSc differences in the degree of protease resistance, aggregation state, or conformational stability.
Objectives. To establish across the phenotypic spectrum of human prion disease: (1) whether and to what extent distinct PrPSc isoforms differ in protease-resistance; (2) whether and to what extent this PrPSc property is related to the aggregation state of the protein and (3) the relative amount of PK-sensitive PrPSc.
Materials and Methods. Frontal cortex PrPSc from the whole spectrum of sCJD subtypes, vCJD and VPsPr (MM and MV codon 129 genotypes) was purified through sample dilution in Sarkosyl and sequential ultracentrifugation in sucrose cushion and pellet resuspensions by sonication. PrPSc aggregates of different size were isolated after ultracentrifugation in sucrose gradient and fraction (12) collection. Whole purified samples and selected fractions of the sucrose gradient preparation were digested using a wide range of PK activities. A curve or "profile" of PrPSc digestion and the corresponding ED50 (PK activity required to decrease PrPSc by 50%) were obtained for each human strain analyzed.
Results. Protease resistance varied significantly among the TSE groups analysed, being highest in vCJD and sCJDVV2 and lowest in sCJDVV1. Fractions 1–4 always contained a fully PK-sensitive form of PrPSc (PrP-sen). However, PrP-sen only accounted for less than 10% of total purified PrPSc in all subtypes analyzed. Overall, the more "sensitive" subtypes contained a larger proportion of "small" PrPSc aggregates 82 Prion Volume 5 Supplement
(fractions 1–6) with respect to the more "resistant" ones. Nevertheless, PK-resistant aggregates of equal size (fractions 6, 9 and 12) extracted from sCJDMM1 and VV2 maintained, at least in part, the different degree of resistance.
Discussion. Our results indicate that: (1) only a limited portion of PrPSc associated to the majority of human prion strains is fully protease sensitive; (2) the analyses of PrP-sen does not differentiate among human prion strains; (3) the PrPSc forms associated to distinct human prion strains show a significant heterogeneity in the degree of protease resistance, which is at least partially explained by their differing aggregation state.
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PPo2-17: Atypical H-type BSE Infection in Bovine-PrP Transgenic Mice Let to the Emergence of Classical BSE Strain Features
Juan Carlos Espinosa,1 Olivier Andréoletti,2 Caroline Lacroux,2 Irene Prieto,1 Patricia Lorenzo,1 Magdalena Larska,1 Thierry Baron3 and Juan María Torres1
1Centro de Investigación en Sanidad Animal; INIA; Valdeolmos, Madrid Spain; 2UMR INRA-ENVT 1225; Interactions Hôte Agent Pathogène; Ecole Nationale Vétérinaire de; Toulouse, France; 3Agence Francaise de Sécurité Sanitaire des Aliments; Lyon Cedex, France
Key words: atypical BSE, PrPres, prion strain, prion transmission
Until identification of atypical cases of Bovine Spongiform Encephalopathy (BSE) in several countries it was assumed that BSE in cattle consisted of only a unique and biologically homogeneous strain type that caused BSE epidemic in Europe. Currently, beside the classical BSE strain associated to most described cases, atypical BSE cases are identified as H- or L-type based on the differences in the western blot profiles of abnormal protease-resistant prion protein (PrPres) according to the apparent molecular mass of its unglycosilated band. In the present study, we characterized five atypical BSE-H isolates by analyzing their molecular and neuropathological properties after transmission in transgenic mice expressing homologous bovine prion protein (PrP). The results showed that most of the inoculated animals conserved the atypical BSE-H strain features. However, a number of animals inoculated with two of these isolates showed prion strain features resembling those of classical BSE in this mouse model. On each case, the strain characteristics were preserved after subsequent passage in the same mice. These data suggest that atypical BSE-H prions, can acquire epidemic BSE-like properties during propagation in a homologous bovine PrP context. Beside a new view on BSE strains diversification, our observations support the hypothesis that atypical BSE-H, which could be a sporadic form of prion disease in cattle, may be at the origin of the foodborne BSE epizooty.
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http://www.prion2011.ca/files/PRION_2011_-_Posters_(May_5-11).pdf
An autopsied case of V180I Creutzfeldt-Jakob disease presenting with panencephalopathic-type pathology and a characteristic prion protein type
Yasushi Iwasaki1,*, Keiko Mori1, Masumi Ito1, Masamitsu Nagaoka2, Toshiaki Ieda3, Tetsuyuki Kitamoto4, Mari Yoshida5, Yoshio Hashizume5Article first published online: 27 JAN 2011 DOI: 10.1111/j.1440-1789.2010.01192.x © 2011 Japanese Society of Neuropathology
Keywords: akinetic mutism state; Creutzfeldt-Jakob disease; panencephalopathic-type; prion protein type; V180I A 73-year-old Japanese woman showed slowly progressive aphasia, apraxia and dementia. She had no family history of prion disease or dementia. One year later she showed parkinsonism and corticobasal degeneration was initially suspected. On MRI, the left temporal neocortex seemed swollen on T2-weighted images in the initial stage, and a later high-signal intensity region was observed in the cerebral cortex in diffusion-weighted images. The patient developed myoclonus and an akinetic mutism state 15 months and 22 months after onset, respectively. Consecutive electroencephalography revealed no periodic sharp-wave complexes. Prion protein (PrP) gene analysis revealed a valine to isoleucine point mutation at codon 180, and methionine homozygosity at codon 129. This patient's clinical symptoms and disease course were atypical for Creutzfeldt–Jakob disease (CJD), and a stable state with nasal tube-feeding lasted several years. She died of respiratory failure at the age of 81, 102 months after the onset. Autopsy revealed widespread spongiform degeneration with weak synaptic-type PrP deposition, confirming the diagnosis of genetic CJD. Neurons in the cerebral cortex were relatively preserved in number and hypertrophic astrocytosis was generally moderate for such long-term disease, but cerebral white matter showed diffuse severe myelin pallor with tissue rarefaction suggestive of panencephalopatic-type pathology. The cerebellar cortex was relatively well preserved with observation of mild spongiform change in the molecular layer, moderate neuron loss in the Purkinje neuron layer, and scattered small plaque-like PrP deposition. Western blot analysis of protease-resistant PrP showed a characteristic pattern without a diglycoform band. V180I CJD is an interesting form of genetic CJD with regards to the clinicopathologic, molecular and genetic findings
http://onlinelibrary.wiley.com/doi/10.1111/j.1440-1789.2010.01192.x/abstract
Neurobiology of Aging Volume 32, Issue 11 , Pages 2006-2015, November 2011.
Age-related alterations affect the susceptibility of mice to prion infection
Dana Avrahami , Ruth Gabizon
Received 12 July 2009; received in revised form 10 December 2009; accepted 21 December 2009. published online 04 January 2010.
Abstract
The sporadic and familial forms of Creutzfeldt-Jacob disease (sCJD and fCJD) usually appear at older ages (60–70 years and ~50, respectively). Nevertheless, infectious forms such as Kuru and variant CJD (vCJD) present mostly at a much earlier age. To study the effect of age on the pathogenesis of infectious prion disease, we inoculated young and aged mice intraperitoneally with RML prions, followed them to disease end point and studied their disease characteristics. We now show that mice infected at older age present a significantly longer incubation time then mice infected at young age. Additionally, brains of mice infected at older age present significantly less disease-specific pathological markers such as gliosis, vacuolation and PrPSc accumulation. Concomitantly, gene expression analysis revealed that the upregulation of disease-associated inflammatory and stress-response genes, was significantly less pronounced in the brains of mice infected at older age. Based on this data, we suggest that alterations associated with aging, are accountable for the delay in the disease onset and the milder pathology in prion-infected aged mice.
Keywords: Prion infection, Scrapie, CJD, Aging, Age-related, Incubation period, Gene expression, Inflammation, PrP, Neurodegeneration
Age-related alterations affect the susceptibility of mice to prion infection
Dana Avrahami, Ruth Gabizon, Neurobiology of Aging, 32:11:2006-2015 (November 2011)
http://www.neurobiologyofaging.org/article/S0197-4580(09)00408-4/abstract
PPo5-29:
Neuropathological and Biochemical Characterization of Unusual Cases of Creutzfeldt-Jakob Disease in Young, Prnp 129 mm Subjects
Fabio Moda,1 Giorgio Giaccone,1 Giuseppe Di Fede,1 Alessandro Terruzzi,2 Silvia Suardi1 and Fabrizio Tagliavini1 1Fondazione IRCCS Istituto Neurologico Carlo Besta; Milano, Italy; 2Policlinico S. Marco; Bergamo, Italy
Key words: sporadic Creutzfeldt-Jakob disease, immunohistochemistry, prion disease, prion protein, PRNP, PrP types
Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common prion disease of humans with the greatest incidence between 60 and 70 years of age. Different polymorphisms (Methionine/Valine) at codon 129 of PRNP gene and PrPSc type are associated with different disease phenotypes. Approximately 95% of the sporadic 129MM CJD patients have PrPSc type 1 (Parchi classification). Young patients with sCJD are extremely rare, and most of them are 129VV with type 1 PrPSc deposition in the brain. We observed two young patients with CJD (age at death 25 and 34 years) who had not the characteristics of variant CJD neither an history of risk factors for iatrogenic transmission. Both were MM at codon 129, without mutation of the PRNP gene. The clinical course was rather long (26 and 28 months), dominated by behavioral disturbances in the early stage and remarkable for the absence of hallmarks of CJD at CSF analysis, MRI and EEG. These two atypical CJD patients were subjected to biochemical and immunohistochemical analysis. Preliminary results evidenced: (i) presence of type 2A PrPSc with the immunohistochemical counterpart of diffuse, finely granular, synaptic pattern of staining, without any focal perivacuolar PrP deposition; (ii) sparing of basal ganglia and cerebellum; (iii) absence of reactivity with a monoclonal antibody (12B2) specific for type 1 PrPSc. These findings may contribute to clarify the relationship between type of PrPSc, patterns and entity of PrP deposition, distribution and severity of the neuropathological changes and their role in the pathogenesis of prion diseases.
http://www.prion2011.ca/files/PRION_2011_-_Posters_(May_5-11).pdf
Wednesday, May 18, 2011
Variably Protease-Sensitive Prionopathy: a Novel Disease of the Prion Protein
17 May 2011
Journal of Molecular Neuroscience DOI: 10.1007/s12031-011-9543-1
http://transmissiblespongiformencephalopathy.blogspot.com/2011/05/variably-protease-sensitive-prionopathy.html
Friday, September 23, 2011
Bovine spongiform encephalopathy associated insertion/deletion polymorphisms of the prion protein gene in the four beef cattle breeds from North China
http://transmissiblespongiformencephalopathy.blogspot.com/2011/09/bovine-spongiform-encephalopathy.html
Sunday, September 25, 2011
Clinical Heidenhain Variant Of Sporadic Creutzfeldt-Jakob Disease (CJD) With Co-occurrence Of Prion Protein Types 1 and 2
http://creutzfeldt-jakob-disease.blogspot.com/2011/09/clinical-heidenhain-variant-of-sporadic.html
Variably protease-sensitive prionopathy in a PRNP codon 129 heterozygous UK patient with co-existing tau, a synuclein and AB pathology
Mark W. Head . Suzanne Lowrie . Gurjit Chohan . Richard Knight . David J. Scoones . James W. Ironside
Received: 28 September 2010 / Revised: 20 October 2010 / Accepted: 21 October 2010 / Published online: 3 November 2010
Springer-Verlag 2010
Keywords Protease-sensitive prionopathy Creutzfeldt-Jakob disease Prion protein PRNP codon 129 Alzheimer's disease Lewy body disease
In 2008 a novel human prion disease, termed proteinasesensitive prionopathy (PSPr) was reported [2]. Affected patients had no known risk factors for prion exposure and no mutations in the prion protein gene (PRNP), but all were VV at codon 129 of PRNP [2]. Subsequently, we prospectively identified a similar case in the UK [3] and another was identified retrospectively from Holland [4]. The effect of PRNP codon 129 on the PSPr phenotype has been recently reported in a further series including six MV and three MM genotypes [6]. The authors identified genotypic effects on clinical, pathological and biochemical features and proposed renaming the condition ''variably protease-sensitive prionopathy'' (VPSPr) [6]. Neuropathological features in VPSPr include minimal spongiform change, minimal gliosis, microplaques in the cerebellum, and prion protein accumulation as coarse aggregates, granules and microplaques. However, the defining feature of VPSPr is the presence of abnormal prion protein (PrPSc) that is less protease-resistant than in other human prion diseases, resulting in a faint ladder of low molecular weight prion protein core fragments. We describe a second VPSPr UK patient, identified prospectively, who is MV at PRNP codon 129, with some atypical pathological features. The patient developed neurological symptoms at the age of 76 and died after 12 months. Initial symptoms were forgetfulness, a tendency to drift off the subject in conversation, and visuo-spatial perceptual problems. His MMSE was recorded as 22/30 at 2 months; at 4 months, he had walking difficulties. At 6 months, he was quiet, withdrawn, could not write his name and at 8 months his MMSE was 10/30. At 9 months, he required assistance for walking, had an action tremor in his arms and urinary incontinence. By 11 months, he was bed-bound, virtually mute. Routine investigations were normal. At 10 months, an EEG was non-specifically abnormal and a CSF examination showed an elevated total protein level, but no other abnormality (14-3-3 negative; S100b normal). A cerebral MRI showed no abnormality. There was no obvious family history of prion disease; consent for full PRNP gene sequencing was not obtained.
Frozen frontal cortex was available for Western blot analysis. Prion protein (PrP) was readily detectable in the absence of proteinase K digestion, but PrPres was not detected initially, even after centrifugal enrichment [3, 4]. Further Western blot analysis showed a faint ladder-like appearance of bands similar to those seen in VPSPr, although the overall intensity was low (Fig. 1).
These biochemical characteristics are indicative of VPSPr. However, the neuropathology differs from previous cases [2-4, 6] (Fig. 2). No PrP microplaques or other prion disease pathology were evident in the cerebellum using anti-PrP antibodies 3F4, 12F10 and KG9 with and without protease digestion. However, microplaques, synaptic and granular PrP deposits were present in the cerebral cortex, basal ganglia and thalamus. There was diffuse Lewy body pathology (neocortical, moderate severity) [5], with Ab plaques (corresponding to CERAD NP probable) and a widespread amyloid angiopathy. Tau pathology was transentorhinal, corresponding to Braak stage 2, with no subcortical or glial tau pathology [1]. No colocalisation of either Ab or tau with the PrP microplaques was observed. The significance of this co-existing neuropathology on the clinicopathological phenotype is uncertain; Lewy body, tau and Ab pathology has been identified in other forms of human prion diseases, but only Ab has so far been reported in VPSPr [6].
Our case does not exhibit pathology typical of VPSPr PRNP codon 129 MV cases hitherto reported [6]: the relative sparing of the cerebellum is particularly striking, along with the other features of neurodegeneration involving tau, Ab and a synuclein. Nevertheless, the biochemistry and cerebral pathology of this case strongly suggest that this is the first identified case of VPSPr in a PRNP codon 129 heterozygote in the UK. Continuing surveillance is essential for the identification of future cases of VPSPr and the investigation of their relationship to other human prion diseases and other neurodegenerative disorders.
Acknowledgments We are grateful to the patient's relatives for giving consent for publication of this report. This is an independent report commissioned and funded by the Policy Research Programme in the Department of Health, UK. The views expressed in the publication are those of the authors and not necessarily those of the Department of Health.
References
snip...see full text ;
http://www.springerlink.com/content/lh16741510468466/fulltext.pdf
* There was no obvious family history of prion disease, ??? ...end...TSS
Wednesday, May 18, 2011
Variably Protease-Sensitive Prionopathy: a Novel Disease of the Prion Protein 17 May 2011
http://prionopathy.blogspot.com/2011/05/variably-protease-sensitive-prionopathy.html
Sunday, November 28, 2010
Variably protease-sensitive prionopathy in a PRNP codon 129 heterozygous UK patient with co-existing tau, a synuclein and AB pathology
http://prionopathy.blogspot.com/2010/11/variably-protease-sensitive-prionopathy.html
Thursday, November 19, 2009
Inherited Creutzfeldt-Jakob disease in a Dutch patient with a novel five octapeptide repeat insertion and unusual cerebellar morphology
J Neurol Neurosurg Psychiatry 2009;80:1386-1389 doi:10.1136/jnnp.2008.169359
Short report
Inherited Creutzfeldt-Jakob disease in a Dutch patient with a novel five octapeptide repeat insertion and unusual cerebellar morphology
C Jansen1, J C van Swieten2, S Capellari3, R Strammiello3, P Parchi3, A J M Rozemuller1 + Author Affiliations
1Dutch Surveillance Centre for Prion Diseases, University Medical Centre Utrecht, Utrecht, The Netherlands 2Department of Neurology, Erasmus University Medical Centre, Rotterdam, The Netherlands 3Dipartimento di Scienze Neurologiche, Università di Bologna, Bologna, Italy Correspondence to Dr C Jansen, Dutch Surveillance Centre for Prion Diseases, University Medical Centre Utrecht, Heidelberglaan 100, PO Box 85500, 3508 GA, Utrecht, The Netherlands; c.jansen@umcutrecht.nl Received 2 December 2008 Revised 22 February 2009 Accepted 5 March 2009
Abstract
An atypical case of inherited Creutzfeldt-Jakob disease (CJD) is described in a 35-year-old Dutch woman, homozygous for methionine at codon 129 of the prion protein gene (PRNP). The clinical phenotype was characterised by slowly progressive cognitive decline and parkinsonism. Neuropathological findings consisted of scanty spongiosis and only faint to absent immunohistochemical staining for the abnormal prion protein, PrPSc, with patchy deposits in the cerebellar cortex. Purkinje cells were abnormally located in the molecular layer of the cerebellum. Western blot analysis showed the co-occurrence of PrPSc types 1 and 2 with an unusual distribution. Sequence analysis disclosed a novel 120 bp insertion in the octapeptide repeat region of the PRNP, encoding five additional R2 octapeptide repeats. These features define an unusual neuropathological phenotype and novel genotype, further expanding the spectrum of genotype-phenotype correlations in inherited prion diseases and emphasising the need to carry out pre-mortem PRNP sequencing in all young patients with atypical dementias....
http://sporadicffi.blogspot.com/2009/11/inherited-creutzfeldtjakob-disease-in.html
The 5-OPRI mutation in this patient was probably inherited in an autosomal dominant pattern but a positive family history in patients with inherited prion disease is not obligate....???...TSS
GEN-07
SPORADIC FATAL INSOMNIA IN A FATAL FAMILIAL INSOMNIA PEDIGREE
S. Capellari1a, P. Cortelli1, P. Avoni1, G.P. Casadei2, A. Baruzzi1, E. Lugaresi1, M. Pocchiari3, P. Gambetti4, P. Montagna1, P. Parchi1. 1Department of Neurological Sciences, University of Bologna, Bologna, Italy; 2Department of Cell Biology and Neurosciences, ISS, Roma, Italy; 3Servizio di Anatomia Patologica, Ospedale Maggiore, Bologna, Italy, 4Division of Neuropathology, CWRU, Cleveland, OH, USA. a mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000208/!x-usc:mailto:capellari@neuro.unibo.it
We describe a case of sporadic fatal insomnia (sFI) occurring in a family in which several members carried the D178N mutation in the PRNP gene and died of fatal familial insomnia (FFI). A 43-year-old woman presented with an 11-month history of diplopia, withdrawal, confusion, memory loss, unsteady gait and inability to sleep with episodes of agitation and dream enactment. After a progressive course characterized by cognitive impairment, marked gait ataxia, signs of autonomic hyperactivity, and myoclonus the patient died 24 months after the onset of symptoms. The patient did not have any personal contact with FFI affected relatives and her closest one was a paternal uncle, the son of her grand-grand mother. Analyses of DNA from various tissues of endo- ecto- and meso-dermal origin, including 5 different regions of the CNS revealed no pathogenic mutations and methionine homozygosity at codon 129 of PRNP. Brain histopathology and PrPSc typing showed typical features of FI such as thalamic and olivary atrophy, focal spongiform degeneration limited to the cerebral cortex, relative sparing of basal ganglia and cerebellum, and relatively low amount of PrPSc type 2A accumulation. sFI represents the rarest among the sporadic human TSE subtypes described to date with less than twenty cases described worldwide and only three cases diagnosed in Italy since the establishment of TSE surveillance. Similarly, only six unrelated FFI families have been observed in Italy to date, making the probability of a chance association between sFI and FFI in the same family extremely low. Thus, we believe that our observation emphasizes the importance of undiscovered factors modulating the susceptibility to human prion diseases.
Supported by the EU Network of Excellence "NeuroPrion" (FOOD-CT-2004-506579).
http://www.neuroprion.com/pdf_docs/conferences/prion2006/abstract_book.pdf
O.10.5
A novel human prion disease affecting subjects with the three prion protein codon 129 genotypes: could it be the sporadic form of Gerstmann-Straussler?
Pierluigi Gambetti Case Western Reserve University, USA
Background: We recently described a novel prion disease, named protease-sensitive prionopathy or PSPr, characterized by the presence of an abnormal prion protein (PrP) that was 60 fold less protease resistant than that of sporadic Creutzfeldt-Jakob disease (sCJD) and on immunoblot generated a distinct ladder-like profile. All affected subjects where homozygous for valine at codon 129 (VV) and had no mutation in the PrP gene.
Methods: We have characterized several new cases in our surveillance and received from Europe.
Results: 1) A disease overall similar to that reported in the 129VV subjects also affects subjects that are methionine/valine heterozygous (MV) and methionine homozygous (MM) at codon 129 and have no PrP gene mutation; 2) The clinical and histopathological features of the new MV and MM PSPr cases are similar but distinguishable from those of the original VV cases; 3) The electrophoretic profiles generated by the abnormal PrP isoforms associated with the MV and MM cases are similar to VV cases but show increasing levels of proteaseresistance; 3) abnormal tau is present in all three genotypic forms of PSPr with features apparently similar to those of primary tauopathies placing PSPr at the intersection of tauopathies and prion diseases.
Discussion: Will focus on: 1) the features of the abnormal PrP in the newly discovered 129MV and 129MM PSPr; 2) the effect of the 129 polymorphism on PSPr compared to that on sCJD; 3) the relationship of PSPr with tauopathies; 4) whether PSPr now with the three 129 genotypic forms is the long sought sporadic form of GSS.
(Supported by NIH AG-14359, NS052319, CDC UR8/CCU515004).
http://www.neuroprion.org/resources/pdf_docs/conferences/prion2009/prion2009_bookofabstracts.pdf
A case of sporadic Creutzfeldt-Jakob disease with a Gerstmann-Sträussler-Scheinker phenotype but no alterations in the PRNP gene
P. P. Liberski · M. Barcikowska · L. Cervenakova · J. Bratosiewicz · M. Marczewska · P. Brown · D. C. Gajdusek
Acta Neuropathol (1998) 96 : 425-430 © Springer-Verlag 1998 Received: 15 July 1997 / Revised, accepted: 24 March 1998
Key words Prions · Creutzfeldt-Jakob disease · Gerstmann-Sträussler-Scheinker disease
Abstract
We report here an unusual sporadic case of Creutzfeldt-Jakob disease (CJD) characterized by an abundance of prion protein (PrP)-immunopositive kuru and multicentric but not florid plaques. Molecular genetic analysis of the PRNP open reading frame region spanning codons 8-221 was performed. Neither deletion nor insertion mutations were detected in the repeat area of the PRNP. No pathogenic mutation was found in the sequenced region between codon 108-221. Restriction analysis of the amplified fragment using restriction endonucleases DdeI, PvuII and AluI did not show any of the previously described pathogenic mutations at codon 102, 105, and 117 associated with Gerstmann-Sträussler-Scheinker (GSS). The patient was heterozygous for the methionine/ valine coding triplet at polymorphic codon 129 of the PRNP gene by sequence, restriction endonuclease analysis and hybridization with allele-specific nucleotides. Furthermore, hybridization with 32P-labeled allele-specific oligonucleotides confirmed the absence of pathogenic mutations at codons 102, 200 and 178. Such a case may present a missing "link" between sporadic CJD and familial GSS.
http://www.springerlink.com/content/wf78le2x9khv6krb/
Ann Neurol. 2010 Aug;68(2):162-72.
Variably protease-sensitive prionopathy: a new sporadic disease of the prion protein.
Zou WQ, Puoti G, Xiao X, Yuan J, Qing L, Cali I, Shimoji M, Langeveld JP, Castellani R, Notari S, Crain B, Schmidt RE, Geschwind M, Dearmond SJ, Cairns NJ, Dickson D, Honig L, Torres JM, Mastrianni J, Capellari S, Giaccone G, Belay ED, Schonberger LB, Cohen M, Perry G, Kong Q, Parchi P, Tagliavini F, Gambetti P.
Department of Pathology, National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, OH 44106, USA. wenquan.zou@case.edu
Abstract OBJECTIVE: The objective of the study is to report 2 new genotypic forms of protease-sensitive prionopathy (PSPr), a novel prion disease described in 2008, in 11 subjects all homozygous for valine at codon 129 of the prion protein (PrP) gene (129VV). The 2 new PSPr forms affect individuals who are either homozygous for methionine (129MM) or heterozygous for methionine/valine (129MV).
METHODS: Fifteen affected subjects with 129MM, 129MV, and 129VV underwent comparative evaluation at the National Prion Disease Pathology Surveillance Center for clinical, histopathologic, immunohistochemical, genotypical, and PrP characteristics.
RESULTS: Disease duration (between 22 and 45 months) was significantly different in the 129VV and 129MV subjects. Most other phenotypic features along with the PrP electrophoretic profile were similar but distinguishable in the 3 129 genotypes. A major difference laid in the sensitivity to protease digestion of the disease-associated PrP, which was high in 129VV but much lower, or altogether lacking, in 129MV and 129MM. This difference prompted the substitution of the original designation with "variably protease-sensitive prionopathy" (VPSPr). None of the subjects had mutations in the PrP gene coding region.
INTERPRETATION: Because all 3 129 genotypes are involved, and are associated with distinguishable phenotypes, VPSPr becomes the second sporadic prion protein disease with this feature after Creutzfeldt-Jakob disease, originally reported in 1920. However, the characteristics of the abnormal prion protein suggest that VPSPr is different from typical prion diseases, and perhaps more akin to subtypes of Gerstmann-Sträussler-Scheinker disease.
PMID: 20695009 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/pubmed/20695009
None of the subjects had mutations in the PrP gene coding region....???...TSS
Sunday, August 24, 2008
P03.121
Sporadic Fatal Insomnia with Unusual Biochemical and Neuropathological Findings
Giaccone, G1; Mangieri, M1; Priano, L2; Limido, L1; Brioschi, A2; Albani, G2; Pradotto, L2; Fociani, P3; Orsi, L4; Mortara, P4; Tagliavini, F1; Mauro, A2 1Fondazione IRCCS Istituto Neurologico Carlo Besta, Italy; 2IRCCS Istituto Auxologico Italiano, Italy; 3Università di Milano, Ospedale Luigi Sacco, Italy; 4Università di Torino, Dipartimento di Neuroscienze, Italy
Sporadic fatal insomnia (SFI) is a rare subtype of human prion disease, whose clinical and neuropathological phenotype is very similar to familial fatal insomnia (FFI). SFI patients reported until now were all homozygous for methionine at codon 129 of PRNP with deposition of type 2 PrPres (Parchi classification) in the brain. Here we describe a 56-year-old woman who died after a 10-month illness characterized by progressive drowsiness, cognitive deterioration, autonomic impairment and myoclonus. Polysomnography demonstrated a pattern similar to that described in FFI cases with loss of circadian pattern of sleep-wake cycle. A remarkable finding was that 20 years before the onset of symptoms, the patient had undergone surgery for a colloid cyst of the third ventricle, and two ventricular shunts were placed, one correctly in the left ventricle, while the second ended in the right thalamus. The PRNP gene showed no mutation and methionine homozygosity at codon 129. The neuropathologic examination revealed neuronal loss, gliosis, and spongiosis that were mild in the cerebral cortex, while relevant in the caudate nucleus, putamen, thalamus, hypothalamus and inferior olives. In the thalamus, the mediodorsal nuclei were more severely affected than the ventral ones. PrPres immunoreactivity was consistent in the striatum, thalamus and hypothalamus, patchy and of low intensity in the cerebral cortex and absent in the cerebellum. Western blot analysis confirmed this topographic distribution of PrPres. The bands corresponding to di- glycosylated, monoglycosylated and non-glycosylated PrPres were equally represented. The nonglycosylated PrPres band had an electrophoretic mobility identical to that of type 1 by Parchi classification, in the multiple cortical and subcortical regions examined. These findings demonstrate the existence of further rare molecular subtypes of human prion diseases, whose characterization may provide clues for the elucidation of the relation between biochemical characteristics of PrPres and clinico-pathological features of these disorders.
http://www.neuroprion.com/pdf_docs/conferences/prion2007/abstract_book.pdf
Greetings,
IT could also be that this sFFI is just another case of iCJD (via friendly fire from the surgery for a colloid cyst of the third ventricle, and two ventricular shunts were placed, one correctly in the left ventricle, while the second ended in the right thalamus), some 20 years before the onset of symptoms of this so called sFFI case, from some sub-type of sporadic CJD, now called sporadic FFI ???
I believe it was Gambetti et al that coined this term sporadic FFI, from some conspicuous sub-type of sporadic CJD possibly? seems they could not tie it to a true FFI by diagnostic standards to date, so it was then termed a sFFI, confusing matters even worse ;
A subtype of sporadic prion disease mimicking fatal familial insomnia
http://www.neurology.org/cgi/content/abstract/52/9/1757?ck=nck
THIS seems to raise more questions than answers, confusing the TSEs even worse.
WHAT is sporadic CJD, and how many sub-types and atypical strains, phenotypes etc. will there be, arising from nothing. a spontaneous happening of sorts???
i think not. ...tss
http://sporadicffi.blogspot.com/
Wednesday, October 27, 2010
A novel variant of human disease with a protease-sensitive prion protein and heterozygosity methionine/valine at codon 129: Case report
snip...
Genetic findings
No mutations were found in the open reading frame after sequencing the prion protein gene (PRNP). A heterozygosis methionine valine (MV) was observed in codon 129.
snip...
http://creutzfeldt-jakob-disease.blogspot.com/2010/10/novel-variant-of-human-disease-with.html
Thursday, July 10, 2008
A Novel Human Disease with Abnormal Prion Protein Sensitive to Protease update July 10, 2008
Although several subjects had family histories of dementia, no mutations were found in the PrP gene open reading frame.
http://cjdmadcowbaseoct2007.blogspot.com/2008/07/novel-human-disease-with-abnormal-prion.html
Thursday, July 10, 2008
A New Prionopathy update July 10, 2008
http://cjdmadcowbaseoct2007.blogspot.com/2008/07/new-prionopathy-update-july-10-2008.html
***+++***
Thursday, July 10, 2008
A Novel Human Disease with Abnormal Prion Protein Sensitive to Protease update July 10, 2008 Friday, June 20, 2008
http://cjdmadcowbaseoct2007.blogspot.com/2008/07/novel-human-disease-with-abnormal-prion.html
Here we go folks. AS predicted. THIS JUST OUT !
Tuesday, August 03, 2010
Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein
http://creutzfeldt-jakob-disease.blogspot.com/2010/08/variably-protease-sensitive-prionopathy.html
Monday, August 9, 2010
Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein or just more PRIONBALONEY ?
snip...see full text ;
http://transmissiblespongiformencephalopathy.blogspot.com/2011/05/variably-protease-sensitive-prionopathy.html
http://prionopathy.blogspot.com/2011/05/variably-protease-sensitive-prionopathy.html
O.K. let's compare some recent cases of this prionpathy in other countries besides Gambetti's first 10 recently, that he claims is a spontaneous event, from a genetic disorder, that is not genetic, but sporadic, that is related to no animal TSE in North America, or the world. ...
http://prionunitusaupdate2008.blogspot.com/2010/08/variably-protease-sensitive-prionopathy.html
Wednesday, October 27, 2010
A novel variant of human disease with a protease-sensitive prion protein and heterozygosity methionine/valine at codon 129: Case report
http://creutzfeldt-jakob-disease.blogspot.com/2010/10/novel-variant-of-human-disease-with.html
Sunday, August 09, 2009
CJD...Straight talk with...James Ironside...and...Terry Singeltary... 2009
http://creutzfeldt-jakob-disease.blogspot.com/2009/08/cjdstraight-talk-withjames.html
Tuesday, August 18, 2009
BSE-The Untold Story - joe gibbs and singeltary 1999 - 2009
http://madcowusda.blogspot.com/2009/08/bse-untold-story-joe-gibbs-and.html
====================================
The familial mutations, Gajdusek proposed, lowered the barrier to such accidental conversion. "Thus," he wrote in 1996, "with these mutations, this ordinarily rare event becomes a ... dominant inherited trait." But Weissmann's qualification still remained to be refuted: the mutations might simply allow easier entry to a lurking virus. ...page 202 Deadly Feast
===================================
something to think about for sure.
but i interpret this as (1st not the gold standard, just my opinion;-), as because of certain gene mutations, one or a family, would be more susceptible to the many different strains of TSE, and the many different proven routes and sources, (which will cause different symptoms, different incubation periods from onset of clinical symptoms to death, different parts of the brain infected, etc.). in other words, it's NOT the gene mutation that CAUSES the disease, but the fact that it makes you more SUSCEPTIBLE, to the TSEs from the surrounding environment, and PLUS accumulation, i think this plays a critical role. maybe there is a one dose scenario, but i think there is more of the 'accumulators' that go clinical, than the 'one dose'. and what is the threshold to sub-clinical to clinical ?
anyway, just pondering out loud here.
also, for anyone interested, there are some studies with links to follow here ;
http://sporadicffi.blogspot.com/
Saturday, June 25, 2011
Transmissibility of BSE-L and Cattle-Adapted TME Prion Strain to Cynomolgus Macaque
"BSE-L in North America may have existed for decades"
http://transmissiblespongiformencephalopathy.blogspot.com/2011/06/transmissibility-of-bse-l-and-cattle.html
Over the next 8-10 weeks, approximately 40% of all the adult mink on the farm died from TME.
snip...
The rancher was a ''dead stock'' feeder using mostly (>95%) downer or dead dairy cattle...
http://web.archive.org/web/20030516051623/http://www.bseinquiry.gov.uk/files/mb/m09/tab05.pdf
Sunday, June 26, 2011
Risk Analysis of Low-Dose Prion Exposures in Cynomolgus Macaque
http://transmissiblespongiformencephalopathy.blogspot.com/2011/06/risk-analysis-of-low-dose-prion.html
Monday, September 26, 2011
L-BSE BASE prion and atypical sporadic CJD
http://bse-atypical.blogspot.com/2011/09/l-bse-base-prion-and-atypical-sporadic.html
PPo2-26:
Transmission of Classical and Atypical (L-type) Bovine Spongiform Encephalopathy (BSE) Prions to Cynomolgus macaques
Fumiko Ono,1 Yoshio Yamakawa,2 Minoru Tobiume,3 Yuko Sato,3 Harutaka Katano,3 Kenichi Hagiwara,2 Iori Itagaki,1 Akio Hiyaoka,1 Katuhiko Komatuzaki,1 Yasunori Emoto,1 Hiroaki Shibata,4 Yuichi Murayama,5 Keiji Terao,4 Yasuhiro Yasutomi4 and Tetsutaro Sata3
1The Corporation for Production and Research of Laboratory Primates; Tsukuba City, Japan; 2Departments of Cell Biology and Biochemistry; and 3Pathology; National Institute of Infectious Diseases; Tokyo, Japan; 4Tsukuba Primate Research Center; National Institute of Biomedical Innovation; Tsukuba City, Japan; 5Prion Disease Research Team; National Institute of Animal Health; Tsukuba City, Japan
Key words: L-type BSE, cBSE, cynomolgus macaques, transmission
BSE prion derived from classical BSE (cBSE) or L-type BSE was characterized by inoculation into the brain of cynomolgus macaques. The neurologic manifestation was developed in all cynomolgus macaques at 27–43 months after intracerebral inoculation of brain homogenate from cBSE-affected cattle (BSE JP/6). Second transmission of cBSE from macaque to macaque shortened incubation period to 13–18 months. cBSE-affected macaques showed the similar clinical signs including hyperekplexia, tremor and paralysis in both primary and second transmission. Two macaques were intracerebrally inoculated brain homogenate from the L-type BSE-affected cattle (BSE JP/24). The incubation periods were 19–20 months in primary transmission. The clinical course of the L-type BSE-affected macaques differed from that in cBSE-affected macaques in the points of severe myoclonus without hyperekplexia. The glycoform profile of PrPSc detected in macaque CNS was consistent with original pattern of either cBSE or L-typeBSE PrPSc, respectively. Although severe spongiform change in the brain was remarkable in all BSE-affected macaques, severe spongiform spread widely in cerebral cortex in L-type BSE-affected macaques. Heavy accumulation of PrPSc surrounded by vacuola formed florid plaques in cerebral cortex of cBSE-affected macaques. Deposit of PrPSc in L-type BSE-affected macaque was weak and diffuse synaptic pattern in cerebrum, but large PrPSc plaques were evident at cerebellum. MRI analysis, T2, T1, DW and flair sequences, at the time of autopsy revealed that brain atrophy and dilatation of cerebral ventricles were significantly severe in L-type BSE-affected macaques. These results suggest that L-type BSE is more virulent strain to primates comparing to cBSE.
http://www.prion2011.ca/files/PRION_2011_-_Posters_(May_5-11).pdf
Identifying Variation in the U.S. Bovine Prion Gene
Bovine spongiform encephalopathy—BSE, or mad cow disease—is a serious threat to the U.S. beef industry.
While the first confirmed case of BSE on U.S. soil in December 2003 had little effect on domestic consumption, it carved into our international beef sales. According to USDA’s Economic Research Service, the United States exported only $552 million worth of beef in 2004—down from $2.6 billion in 2002 and $3.1 billion in 2003—a reduction due, in part, to the BSE case.
Are some cattle more susceptible to BSE? Is there a genetic component involved?
To address these and other questions, ARS scientists at the U.S. Meat Animal Research Center (USMARC) at Clay Center, Nebraska, have sequenced the bovine prion gene, PRNP, in 192 cattle representing 16 beef and 5 dairy breeds common in the United States. This work was partially funded by a grant from USDA’s Cooperative State Research, Education, and Extension Service.
Prions are proteins that occur naturally in mammals. BSE is a fatal neurological disorder characterized by irregularly folded prions. Much is unknown about the disease, but scientists recognize a correlation between variations in the PRNP gene in some mammals and susceptibility to transmissible spongiform encephalopathies, such as scrapie in sheep.
“Evidence indicates that this could also be true in cattle,” says molecular biologist Mike Clawson. He is among the USMARC scientists examining PRNP variation to learn if and how different forms, or alleles, of the prion gene correlate with BSE susceptibility.
A thorough characterization of PRNP variation in a U.S. cattle population will provide a reference framework for researchers to use in analyzing PRNP sequences from cattle afflicted with BSE.
From the 192 PRNP genes sequenced, Clawson and his colleagues have identified 388 variations, or polymorphisms, of which 287 were previously unknown. Some of these polymorphisms may influence BSE susceptibility in cattle, he says. Ongoing studies with European collaborators are testing the newly identified variants for association with BSE. If these studies show some cattle to be genetically less susceptible to the disease, this information could shed light on BSE’s transmission and development.
The United States has had only three confirmed cases of BSE. Laboratory tests showed that the second and third of these appear to differ significantly from the first case, says Clawson.
“By comparing the PRNP sequence from BSE-infected cattle to healthy cattle, we may be able to identify genetic markers in the prion gene that predict BSE susceptibility,” he says.
In addition to PRNP, the team is currently sequencing several genes closely related to it. These too will be tested for their association with BSE.
“The prevalence of BSE in the United States is extremely low and is declining worldwide,” Clawson says. “Well-characterized genetic markers that correlate to resistance could improve our understanding of the disease and prepare the cattle industry to respond if another prion disease arises in the future.”—By Laura McGinnis, Agricultural Research Service Information Staff.
This research is part of Animal Health, an ARS National Program (#103) described on the World Wide Web at www.nps.ars.usda.gov.
Michael L. Clawson is at the USDA-ARS Roman L. Hruska U.S. Meat Animal Research Center, P.O. Box 166, Clay Center, NE 68933; phone (402) 762-4342, fax (402) 762-4375.
"Identifying Variation in the U.S. Bovine Prion Gene" was published in the January 2007 issue of Agricultural Research magazine.
http://seprl.ars.usda.gov/is/AR/archive/jan07/bovine0107.htm?pf=1
Research Project: Susceptibility of Cattle with the E211k Prnp Allele to Bse
Location: Virus and Prion Research Unit
Project Number: 3625-32000-086-14 Project Type: Specific Cooperative Agreement
Start Date: Aug 14, 2008 End Date: Jul 31, 2013
Objective:
The objective of this cooperative research project is to investigate the influence of the bovine Prnp gene polymorphisms, E211K, on the susceptibility to BSE. Specifically, the research project will provide 134 embryos that will be used to generate approximately 62 animals, 31 of which will contain the rare allele for the purposes BSE research. This ongoing SCA with Iowa State University to produce cattle with the E211K Prnp allele for BSE research has resulted in an E211/K211 heterozygous bull. We are now in the unique position to extend our research on this allele to include animals homozygous for K at position 211. Based upon our understanding of this novel polymorphism one would predict homozygotes would have a more rapid onset of clinical signs associated with genetic BSE than heterozygotes.
Approach:
To achieve the research goals it is imperative to increase the number of animals available to study this Prnp polymorphism. One female calf of the 2006 BSE case was identified and carries the E211K allele. The specific objectives are to be accomplished through the production of multiple offspring from this E211K heifer through superovulation and embryo transfer. Approximately 50% of the offspring will be heterozygous for the E211K polymorphism while the others will serve as genetically matched non-E211K controls. Collection of semen from an E211K heterozygous bull will allow creation of E211K homozygotes. To protect this unique resource immediate collection of embryos is necessary. The initial goal is to harvest 134 embryos that should result in approximately 62 pregnancies (half of which will carry the E211K polymorphism) for immediate use in the studies to amplify the E211K material, test for genetic susceptibility to TSE, and develop a breeding group to produce calves for transmissibility studies. To achieve the goal of understanding the role of the E211K polymorphism with regard to genetic BSE we have utilized superovulation and embryo transfer obtaining a E211/K211 containing bull. We are now in a position to collect semen from the E211/K211 heterozygous bull to create K211/K211 homozygotes. To accomplish this goal we plan to collect semen from this bull and through artificial insemination using semen from the E211/K211 bull with superovulation and embryo transplantation using other E211/K211 heterzygotes generate 30-40 embryos resulting in 15-20 pregnancies yielding approximately 5 K211/K211 homozygous animals and 10 E211/K211 heterozyous animals as well as 5 E211/E211 homozygous controls.
http://www.ars.usda.gov/research/projects/projects.htm?accn_no=413249
http://www.cdc.gov/eid/content/15/12/pdfs/2013.pdf
Subject: Identifying Variation in the U.S. Bovine Prion Gene Date: January 22, 2007 at 8:32 am PST
Identifying Variation in the U.S. Bovine Prion Gene By Laura McGinnis January 22, 2007 Do genes affect bovine spongiform encephalopathy?also known as BSE, or "mad cow" disease? Are some cattle more susceptible than others?
To address these and other questions, Agricultural Research Service (ARS) scientists at the U.S. Meat Animal Research Center in Clay Center, Neb., have sequenced the bovine prion gene (PRNP) in 192 cattle that represent 16 beef and five dairy breeds common in the United States.
This work, partially funded by a grant from the U.S. Department of Agriculture's Cooperative State Research, Education and Extension Service, is expanding the understanding of how the disease works.
BSE is a fatal neurological disorder characterized by prions?proteins that occur naturally in mammals?that fold irregularly. Molecular biologist Mike Clawson and his Clay Center colleagues are examining PRNP variation in order to learn if and how prions correlate with BSE susceptibility.
From the 192 PRNP sequences, Clawson and his colleagues have identified 388 variations, or polymorphisms, 287 of which were previously unknown. Some of these polymorphisms may influence BSE susceptibility in cattle.
Comparing PRNP sequences from infected and healthy cattle may enable researchers to identify genetic markers in the prion gene that predict BSE susceptibility. In addition to PRNP, the team is currently sequencing several closely related genes, which will also be tested for their association with BSE.
The prevalence of BSE in the United States is extremely low, but this research could improve understanding of the disease and prepare the cattle industry to respond if another prion disease should arise in the future.
http://www.ars.usda.gov/is/pr/2007/070122.htm
Identifying Variation in the U.S. Bovine Prion Gene
Bovine spongiform encephalopathy (BSE, or mad cow disease) is a serious threat to the U.S. beef industry.
While the first confirmed case of BSE on U.S. soil in December 2003 had little effect on domestic consumption, it carved into our international beef sales. According to USDAs Economic Research Service, the United States exported only $552 million worth of beef in 2004 down from $2.6 billion in 2002 and $3.1 billion in 2003 a reduction due, in part, to the BSE case.
Are some cattle more susceptible to BSE? Is there a genetic component involved?
To address these and other questions, ARS scientists at the U.S. Meat Animal Research Center (USMARC) at Clay Center, Nebraska, have sequenced the bovine prion gene, PRNP, in 192 cattle representing 16 beef and 5 dairy breeds common in the United States. This work was partially funded by a grant from USDA?s Cooperative State Research, Education, and Extension Service.
Prions are proteins that occur naturally in mammals. BSE is a fatal neurological disorder characterized by irregularly folded prions. Much is unknown about the disease, but scientists recognize a correlation between variations in the PRNP gene in some mammals and susceptibility to transmissible spongiform encephalopathies, such as scrapie in sheep.
Evidence indicates that this could also be true in cattle, says molecular biologist Mike Clawson. He is among the USMARC scientists examining PRNP variation to learn if and how different forms, or alleles, of the prion gene correlate with BSE susceptibility.
A thorough characterization of PRNP variation in a U.S. cattle population will provide a reference framework for researchers to use in analyzing PRNP sequences from cattle afflicted with BSE.
From the 192 PRNP genes sequenced, Clawson and his colleagues have identified 388 variations, or polymorphisms, of which 287 were previously unknown. Some of these polymorphisms may influence BSE susceptibility in cattle, he says. Ongoing studies with European collaborators are testing the newly identified variants for association with BSE. If these studies show some cattle to be genetically less susceptible to the disease, this information could shed light on BSEs transmission and development.
The United States has had only three confirmed cases of BSE. Laboratory tests showed that the second and third of these appear to differ significantly from the first case, says Clawson.
By comparing the PRNP sequence from BSE-infected cattle to healthy cattle, we may be able to identify genetic markers in the prion gene that predict BSE susceptibility, he says.
In addition to PRNP, the team is currently sequencing several genes closely related to it. These too will be tested for their association with BSE.
The prevalence of BSE in the United States is extremely low and is declining worldwide, Clawson says. Well-characterized genetic markers that correlate to resistance could improve our understanding of the disease and prepare the cattle industry to respond if another prion disease arises in the future. By Laura McGinnis, Agricultural Research Service Information Staff.
This research is part of Animal Health, an ARS National Program (#103) described on the World Wide Web at www.nps.ars.usda.gov.
Michael L. Clawson is at the USDA-ARS Roman L. Hruska U.S. Meat Animal Research Center, P.O. Box 166, Clay Center, NE 68933; phone (402) 762-4342, fax (402) 762-4375.
http://www.ars.usda.gov/is/AR/archive/jan07/bovine0107.htm
http://www.ars.usda.gov/is/AR/archive/jan07/bovine0107.pdf
Title: Prion gene haplotypes of U.S. cattle
Authors
Clawson, Michael - mike Heaton, Michael - mike Keele, John Smith, Timothy - tim Harhay, Gregory Laegreid, William - will
Submitted to: BioMed Central (BMC) Genetics Publication Type: Peer Reviewed Journal Publication Acceptance Date: October 24, 2006 Publication Date: November 8, 2006 Reprint URL: http://www.biomedcentral.com/1471-2156/7/51 Citation: Clawson, M.L., Heaton, M.P., Keele, J.W., Smith, T.P., Harhay, G.P., Laegreid, W.W. 2006. Prion gene haplotypes of U.S. cattle. BioMed Central (BMC) Genetics. 7:51.
Interpretive Summary: Transmissible spongiform encephalopathies (TSEs) are fatal neurological disorders that are characterized by abnormal deposits of the prion protein. TSEs have been identified in cats, cattle, deer, elk, humans, mink, moose, and sheep. The cattle TSE, bovine spongiform encephalopathy (BSE) is also known as mad cow disease. BSE is the probable cause of the human TSE variant Creutzfeldt-Jakob disease, transmitted from cattle to people via the food chain. Sequence variation in the prion gene correlates with TSE progression in humans, sheep, and mice. Additionally, there is evidence that bovine PRNP variation correlates with BSE progression. In this study, 25.2 kb of PRNP was sequenced from the promoter region through the three prime untranslated region in 192 U.S. cattle (16 beef, five dairy breeds). Three hundred and eighty eight polymorphisms were observed, of which 287 have not been previously reported. A subset of polymorphisms that efficiently tag genetic variation in U.S. cattle was identified. The results of this study provide a reference framework for accurate and comprehensive evaluation of prion gene variation and its relationship to BSE. Technical Abstract: Background: Bovine spongiform encephalopathy (BSE) is a fatal neurological disorder characterized by abnormal deposits of a protease-resistant isoform of the prion protein. Characterizing linkage disequilibrium (LD) and haplotype networks within the bovine prion gene (PRNP) is important for 1) testing rare or common PRNP variation for an association with BSE and 2) interpreting any association of PRNP alleles with BSE susceptibility. The objective of this study was to identify polymorphisms and haplotypes within PRNP from the promoter region through the 3'UTR in a diverse sample of U.S. cattle genomes. Results: A 25.2-kb genomic region containing PRNP was sequenced from 192 diverse U.S. beef and dairy cattle. Sequence analyses identified 388 total polymorphisms, of which 287 have not previously been reported. The polymorphism alleles define PRNP by regions of high and low LD. High LD is present between alleles in the promoter region through exon 2 (6.7 kb). PRNP alleles within the majority of intron 2, the entire coding sequence and the untranslated region of exon 3 are in low LD (18.0 kb). Two haplotype networks, one representing the region of high LD and the other the region of low LD yielded nineteen different combinations that represent haplotypes spanning PRNP. The haplotype combinations are tagged by 19 polymorphisms (htSNPS) which characterize variation within and across PRNP.
Conclusion: The number of polymorphisms in the prion gene region of U.S. cattle is nearly four times greater than previously described. These polymorphisms define PRNP haplotypes that may influence BSE susceptibility in cattle.
http://www.ars.usda.gov/research/publications/publications.htm?seq_no_115=195487
Title: Frequencies of polymorphisms associated with BSE resistance differ significantly between Bos taurus, Bos indicus, and composite cattle
Authors
BRUNELLE, BRIAN GREENLEE, JUSTIN Seabury, Christopher - TEXAS A&M UNIVERSITY Brown Ii, Charles - ABS GLOBAL NICHOLSON, ERIC
Submitted to: BioMed Central (BMC) Veterinary Research Publication Type: Peer Reviewed Journal Publication Acceptance Date: August 22, 2008 Publication Date: August 22, 2008 Citation: Brunelle, B.W., Greenlee, J.J., Seabury, C.M., Brown II, C.E., Nicholson, E.M. 2008. Frequencies of Polymorphisms Associated with BSE Resistance Differ Significantly Between Bos taurus, Bos indicus, and Composite Cattle. BioMed Central (BMC) Veterinary Research. 4(1):36. Available: http://www.biomedcentral.com/1746-6148/4/36.
Interpretive Summary: Bovine spongiform encephalopathy (BSE) is a neurodegenerative prion disease of cattle. There are three host factors related to the host prion protein known to influence susceptibility or resistance to BSE: single amino acid changes in the prion protein, repeat regions within the prion protein, and expression levels of the prion protein. These factors have been well documented in breeds of Bos taurus cattle, but there is little-to-no data on these factors in Bos indicus purebred or Bos indicus x Bos taurus crossbred cattle. Since Bos indicus cattle contribute to the U.S. cattle population, we wanted to determine the frequency of the host factors associated with BSE susceptibility. We studied 58 Bos indicus purebred and 38 Bos indicus x Bos taurus crossbred cattle. The only differences between Bos indicus and Bos taurus cattle were in two factors associated with prion protein expression levels. It was observed that Bos indicus cattle had a much higher frequency of one factor associated with resistance to BSE compared to Bos taurus cattle, while the second factor associated with resistance to BSE was much lower in Bos indicus cattle compared to Bos taurus cattle. This data is useful in determining the relative risk of BSE in Bos indicus cattle based upon these factors. Technical Abstract: Transmissible spongiform encephalopathies (TSEs) are neurodegenerative diseases that affect several mammalian species. At least three factors related to the host prion protein are known to modulate susceptibility or resistance to a TSE: amino acid sequence, atypical number of octapeptide repeats, and expression level. These factors have been extensively studied in breeds of Bos taurus cattle in relation to bovine spongiform encephalopathy (BSE). However, little is currently known about these factors in Bos indicus purebred or B. indicus x B. taurus crossbred cattle. The goal of our study was to establish the frequency of markers associated with enhanced susceptibility or resistance to BSE in B. indicus purebred and crossbred cattle.
http://www.ars.usda.gov/research/publications/publications.htm?SEQ_NO_115=224736
18 January 2007 - Draft minutes of the SEAC 95 meeting (426 KB) held on 7 December 2006 are now available.
snip...
ITEM 9 - ANY OTHER BUSINESS
snip...
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
64. A member noted that at the recent Neuroprion meeting, a study was presented showing that in transgenic mice BSE passaged in sheep may be more virulent and infectious to a wider range of species than bovine derived BSE. Other work presented suggested that BSE and bovine amyloidotic spongiform encephalopathy (BASE) MAY BE RELATED. A mutation had been identified in the prion protein gene in an AMERICAN BASE CASE THAT WAS SIMILAR IN NATURE TO A MUTATION FOUND IN CASES OF SPORADIC CJD. A study also demonstrated that in a mouse model it was possible to alleviate the pathological changes of prion disease by suppressing expression of the prion protein gene after infection.
++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
NOW PLEASE GO BACK AND READ THAT SECOND PARAGRAPH AGAIN.....TSS
http://www.seac.gov.uk/minutes/95.pdf
PLEASE READ FULL TEXT ;
http://www.cdc.gov/ncidod/EID/vol12no12/06-0965.htm?s_cid=eid06_0965_e
Discussion
This study assessed the prevalence of specific BSE-associated factors in B. indicus purebred and composite cattle, which were then compared to frequencies observed in B. taurus cattle. Through PRNP sequence analysis, we surveyed cattle for the presence of an E211K amino acid replacement, as well as the presence of 7 or more octapeptide repeats. In addition, we determined the frequencies of the 23-bp and 12-bp indel regions associated with bovine PRNP transcriptional regulation.
None of the PRNP alleles for the B. indicus samples evaluated in this study exhibited an E211K amino acid replacement or any novel coding region polymorphism. To date, the E211K change has been reported in only two bovine samples, the 2006 Alabama atypical BSE case [7] and its only known living offspring [8]. The affected animal was a composite (B. taurus × B. indicus), but because no parental information is currently available, it is unknown whether the corresponding nucleotide change was inherited or the result of spontaneous mutation. If it was inherited, then the E211K allele may have originated in either a B. taurus ancestor or a B. indicus ancestor. Unfortunately, the data presented here cannot facilitate a species level assignment, as the PRNP coding sequence of the 2006 Alabama case did not possess any species-specific polymorphisms. This particular animal was determined to possess one haplotype with a 23 and 12-bp insertion, and the other with a 23 and 12-bp deletion [27]. These 2 haplotypes occur in 92% of B. taurus, but only in 25% B. indicus cattle (Table ?(Table1),1), as estimated by our analyses. Unless more information becomes available, it cannot be determined where the E211K replacement may have originated.
No B. indicus sample had an octapeptide region containing more than 6 repeats. Notably, humans are the only TSE-susceptible mammal besides the Brown Swiss breed of B. taurus cattle for which additional octapeptide repeats have been observed. Interestingly, a transgenic mouse model expressing bovine PrPC with 1 extra repeat was more susceptible to BSE challenge than a transgenic mouse with the normal number of repeats, but did not develop a spontaneous prion disease [14]. However, a transgenic mouse expressing a bovine PRNP gene encoding 4 additional repeats did in fact develop a spontaneous prion disease [15]. While cattle with 1 additional octapeptide repeat may have an enhanced risk for classical BSE only if exposed to infected material, the appearance of PRNP genes encoding extra octapeptide repeats in any cattle breed may be cause for concern.
The incidence of E211K as well as octapeptide regions with 7 repeats among cattle does not provide a species-level explanation for potential differences in susceptibility to BSE among B. taurus and B. indicus cattle. Therefore, only the 23-bp and 12-bp indel regions seem pertinent in these populations because both of these bovine PRNP sequence regions have been shown to influence transcription levels of PrPC. The B. indicus purebred and composite cattle had a very low frequency of the 23-bp insertion as compared to B. taurus, while only B. indicus purebred cattle had a high frequency of the 12-bp insertion. To date, no consensus has emerged regarding whether one of these bovine PRNP regions is more influential than the other with respect to classical BSE resistance in cattle. Originally, only the 23-bp region was found to be significantly associated with (classical) BSE resistance [26]. Using a reporter gene assay, it was later concluded that the 23-bp indel region was the most relevant locus, as the only constructs that lowered expression levels were those containing the 23-bp insertion [25]. In contrast, other reports indicate the 12-bp indel is more relevant both statistically [24] and in a reporter gene assay [30]. The discrepancy between the significance of these two regions with respect to resistance or susceptibility to classical BSE may be influenced by 3 or more factors. First, the 23-bp and 12-bp regions are physically linked (~2-Kbp apart). Therefore, recombination is most likely rare given the small distance separating the two indel polymorphisms. Moreover, high levels of linkage disequilibrium have been detected for genetic variation within the bovine PRNP promoter and intron 1 [31]. Secondarily, the 23-bp insertion and 12-bp deletion haplotype is absent among cattle surveyed to date, thereby creating an equal-to-greater overall frequency of 12-bp insertions as compared to the frequency spectrum of 23-bp insertions. More specifically, twice as many haplotypes (n = 12) contribute to the overall frequency of the 12-bp intron 1 insertion as those contributing to the frequency of the 23-bp insertion (n = 6; Table ?Table2).2). This may inevitably bias indel association studies. Lastly, species specific allelic variation associated with the genetic backgrounds of B. taurus and B. indicus may differentially interact with the 23-bp promoter and 12-bp intron 1 PRNP polymorphisms, perhaps making each polymorphism more or less relevant in a particular bovine species. On the basis of indel genotype alone, if it is ultimately concluded that the 23-bp insertion has a greater influence than the 12-bp insertion with respect to resistance to classical BSE in cattle following exposure to infected material, B. indicus purebred and composite cattle would be at greater risk than B. taurus cattle. Conversely, if the 12-bp insertion were to modulate a greater level of resistance to BSE, then B. indicus cattle would be at a lower risk than B. taurus and composite cattle.
Other Sections?
Conclusion
We determined the frequencies of known genetic factors associated with differential susceptibility to BSE in B. indicus purebred and B. indicus × B. taurus composite cattle, as compared to B. taurus purebred cattle. No deviations from the expected numbers of octapeptide repeats were detected for B. indicus purebred and composite cattle. Likewise, the E211K substitution was not detected within the PRNP coding sequences for cattle investigated herein. However, a significant difference was detected for a comparison of the 23-bp and 12-bp indel genotype frequencies between B. indicus and B. taurus cattle. The origin of this result could be attributed to significant differences in haplotype frequencies among B. indicus, B. taurus, and composite cattle. Currently, it is unknown which bovine PRNP region (23-bp promoter; 12-bp intron 1), if either, may be more important with respect to differential susceptibility to classical BSE in cattle following exposure to the etiologic agent. Should either the 23-bp promoter region or the 12-bp intron 1 region of the bovine PRNP prove more biologically relevant to the manifestation of disease, substantial heritable differences in overall susceptibility or resistance to classical BSE may exist between B. indicus and B. taurus cattle.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2569919/
let's take a closer look at this new prionpathy or prionopathy, and then let's look at the g-h-BSEalabama mad cow.
This new prionopathy in humans? the genetic makeup is IDENTICAL to the g-h-BSEalabama mad cow, the only _documented_ mad cow in the world to date like this, ......wait, it get's better. this new prionpathy is killing young and old humans, with LONG DURATION from onset of symptoms to death, and the symptoms are very similar to nvCJD victims, OH, and the plaques are very similar in some cases too, bbbut, it's not related to the g-h-BSEalabama cow, WAIT NOW, it gets even better, the new human prionpathy that they claim is a genetic TSE, has no relation to any gene mutation in that family. daaa, ya think it could be related to that mad cow with the same genetic make-up ??? there were literally tons and tons of banned mad cow protein in Alabama in commerce, and none of it transmitted to cows, and the cows to humans there from ??? r i g h t $$$
ALABAMA MAD COW g-h-BSEalabama
In this study, we identified a novel mutation in the bovine prion protein gene (Prnp), called E211K, of a confirmed BSE positive cow from Alabama, United States of America. This mutation is identical to the E200K pathogenic mutation found in humans with a genetic form of CJD. This finding represents the first report of a confirmed case of BSE with a potential pathogenic mutation within the bovine Prnp gene. We hypothesize that the bovine Prnp E211K mutation most likely has caused BSE in "the approximately 10-year-old cow" carrying the E221K mutation.
http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000156
http://www.plospathogens.org/article/fetchObjectAttachment.action?uri=info%3Adoi%2F10.1371%2Fjournal.ppat.1000156&representation=PDF
her healthy calf also carried the mutation (J. A. Richt and S. M. Hall PLoS Pathog. 4, e1000156; 2008).
This raises the possibility that the disease could occasionally be genetic in origin. Indeed, the report of the UK BSE Inquiry in 2000 suggested that the UK epidemic had most likely originated from such a mutation and argued against the scrapierelated assumption. Such rare potential pathogenic PRNP mutations could occur in countries at present considered to be free of BSE, such as Australia and New Zealand. So it is important to maintain strict surveillance for BSE in cattle, with rigorous enforcement of the ruminant feed ban (many countries still feed ruminant proteins to pigs). Removal of specified risk material, such as brain and spinal cord, from cattle at slaughter prevents infected material from entering the human food chain. Routine genetic screening of cattle for PRNP mutations, which is now available, could provide additional data on the risk to the public. Because the point mutation identified in the Alabama animals is identical to that responsible for the commonest type of familial (genetic) CJD in humans, it is possible that the resulting infective prion protein might cross the bovine–human species barrier more easily. Patients with vCJD continue to be identified. The fact that this is happening less often should not lead to relaxation of the controls necessary to prevent future outbreaks.
Malcolm A. Ferguson-Smith Cambridge University Department of Veterinary Medicine, Madingley Road, Cambridge CB3 0ES, UK e-mail: maf12@cam.ac.uk Jürgen A. Richt College of Veterinary Medicine, Kansas State University, K224B Mosier Hall, Manhattan, Kansas 66506-5601, USA
NATURE|Vol 457|26 February 2009
http://www.nature.com/nature/journal/v457/n7233/full/4571079b.html
Saturday, August 14, 2010
BSE Case Associated with Prion Protein Gene Mutation (g-h-BSEalabama) and VPSPr PRIONPATHY
(see mad cow feed in COMMERCE IN ALABAMA...TSS)
http://prionpathy.blogspot.com/2010/08/bse-case-associated-with-prion-protein.html
P.9.21
Molecular characterization of BSE in Canada
Jianmin Yang1, Sandor Dudas2, Catherine Graham2, Markus Czub3, Tim McAllister1, Stefanie Czub1 1Agriculture and Agri-Food Canada Research Centre, Canada; 2National and OIE BSE Reference Laboratory, Canada; 3University of Calgary, Canada
Background: Three BSE types (classical and two atypical) have been identified on the basis of molecular characteristics of the misfolded protein associated with the disease. To date, each of these three types have been detected in Canadian cattle.
Objectives: This study was conducted to further characterize the 16 Canadian BSE cases based on the biochemical properties of there associated PrPres. Methods: Immuno-reactivity, molecular weight, glycoform profiles and relative proteinase K sensitivity of the PrPres from each of the 16 confirmed Canadian BSE cases was determined using modified Western blot analysis.
Results: Fourteen of the 16 Canadian BSE cases were C type, 1 was H type and 1 was L type. The Canadian H and L-type BSE cases exhibited size shifts and changes in glycosylation similar to other atypical BSE cases. PK digestion under mild and stringent conditions revealed a reduced protease resistance of the atypical cases compared to the C-type cases. N terminal- specific antibodies bound to PrPres from H type but not from C or L type. The C-terminal-specific antibodies resulted in a shift in the glycoform profile and detected a fourth band in the Canadian H-type BSE.
Discussion: The C, L and H type BSE cases in Canada exhibit molecular characteristics similar to those described for classical and atypical BSE cases from Europe and Japan. This supports the theory that the importation of BSE contaminated feedstuff is the source of C-type BSE in Canada. *It also suggests a similar cause or source for atypical BSE in these countries.
http://www.prion2009.com/sites/default/files/Prion2009_Book_of_Abstracts.pdf
NOW, LET'S LOOK AT A FEW 100S OF TONS OF THESE BANNED SUSPECT MAD COW FEED IN COMMERCE IN THE USA ;
BANNED SUSPECT MAD COW FEED IN COMMERCE 2006-2007, SOME 10 YEARS AFTER THE INFAMOUS PARTIAL AND VOLUNTARY MAD COW FEED BAN or August 4, 1997, that was nothing more than ink on paper, so really, there was no BSE triple fire wall at all, and this was improving ???
*** BANNED MAD COW FEED IN THE USA IN COMMERCE TONS AND TONS
THIS is just ONE month report, of TWO recalls of prohibited banned MBM, which is illegal, mixed with 85% blood meal, which is still legal, but yet we know the TSE/BSE agent will transmit blood. we have this l-BSE in North America that is much more virulent and there is much concern with blood issue and l-BSE as there is with nvCJD in humans. some are even starting to be concerned with sporadic CJD and blood, and there are studies showing transmission there as well. ... this is one month recall page, where 10 MILLION POUNDS OF BANNED MAD COW FEED WENT OUT INTO COMMERCE, TO BE FED OUT. very little of the product that reaches commerce is ever returned via recall, very, very little. this was 2007, TEN YEARS AFTER THE AUGUST 4, 1997, PARTIAL AND VOLUNTARY MAD COW FEED BAN IN THE USA, that was nothing but ink on paper. i have listed the tonnage of mad cow feed that was in ALABAMA in one of the links too, this is where the infamous g-h-BSEalabama case was, a genetic relation matching the new sporadic CJD in the USA. seems this saga just keeps getting better and better.......$$$
10,000,000+ LBS. of PROHIBITED BANNED MAD COW FEED I.E. BLOOD LACED MBM IN COMMERCE USA 2007
Date: March 21, 2007 at 2:27 pm PST
RECALLS AND FIELD CORRECTIONS: VETERINARY MEDICINES -- CLASS II
___________________________________
PRODUCT
Bulk cattle feed made with recalled Darling's 85% Blood Meal, Flash Dried, Recall # V-024-2007
CODE
Cattle feed delivered between 01/12/2007 and 01/26/2007
RECALLING FIRM/MANUFACTURER
Pfeiffer, Arno, Inc, Greenbush, WI. by conversation on February 5, 2007.
Firm initiated recall is ongoing.
REASON
Blood meal used to make cattle feed was recalled because it was cross- contaminated with prohibited bovine meat and bone meal that had been manufactured on common equipment and labeling did not bear cautionary BSE statement.
VOLUME OF PRODUCT IN COMMERCE
42,090 lbs.
DISTRIBUTION
WI
___________________________________
PRODUCT
Custom dairy premix products: MNM ALL PURPOSE Pellet, HILLSIDE/CDL Prot- Buffer Meal, LEE, M.-CLOSE UP PX Pellet, HIGH DESERT/ GHC LACT Meal, TATARKA, M CUST PROT Meal, SUNRIDGE/CDL PROTEIN Blend, LOURENZO, K PVM DAIRY Meal, DOUBLE B DAIRY/GHC LAC Mineral, WEST PIONT/GHC CLOSEUP Mineral, WEST POINT/GHC LACT Meal, JENKS, J/COMPASS PROTEIN Meal, COPPINI - 8# SPECIAL DAIRY Mix, GULICK, L-LACT Meal (Bulk), TRIPLE J - PROTEIN/LACTATION, ROCK CREEK/GHC MILK Mineral, BETTENCOURT/GHC S.SIDE MK-MN, BETTENCOURT #1/GHC MILK MINR, V&C DAIRY/GHC LACT Meal, VEENSTRA, F/GHC LACT Meal, SMUTNY, A- BYPASS ML W/SMARTA, Recall # V-025-2007
CODE
The firm does not utilize a code - only shipping documentation with commodity and weights identified.
RECALLING FIRM/MANUFACTURER
Rangen, Inc, Buhl, ID, by letters on February 13 and 14, 2007. Firm initiated recall is complete.
REASON
Products manufactured from bulk feed containing blood meal that was cross contaminated with prohibited meat and bone meal and the labeling did not bear cautionary BSE statement.
VOLUME OF PRODUCT IN COMMERCE
9,997,976 lbs.
DISTRIBUTION
ID and NV
END OF ENFORCEMENT REPORT FOR MARCH 21, 2007
http://www.fda.gov/Safety/Recalls/EnforcementReports/2007/ucm120446.htm
Saturday, November 6, 2010
TAFS1 Position Paper on Position Paper on Relaxation of the Feed Ban in the EU Berne, 2010 TAFS
INTERNATIONAL FORUM FOR TRANSMISSIBLE ANIMAL DISEASES AND FOOD SAFETY a non-profit Swiss Foundation
http://madcowfeed.blogspot.com/2010/11/tafs1-position-paper-on-position-paper.html
Archive Number 20101206.4364 Published Date 06-DEC-2010 Subject PRO/AH/EDR> Prion disease update 2010 (11)
PRION DISEASE UPDATE 2010 (11)
http://www.promedmail.org/pls/apex/f?p=2400:1001:5492868805159684::NO::F2400_P1001_BACK_PAGE,F2400_P1001_PUB_MAIL_ID:1000,86129
Saturday, July 23, 2011
CATTLE HEADS WITH TONSILS, BEEF TONGUES, SPINAL CORD, SPECIFIED RISK MATERIALS (SRM's) AND PRIONS, AKA MAD COW DISEASE
http://transmissiblespongiformencephalopathy.blogspot.com/2011/07/cattle-heads-with-tonsils-beef-tongues.html
Wednesday, July 28, 2010
Atypical prion proteins and IBNC in cattle DEFRA project code SE1796 FOIA Final report
http://bse-atypical.blogspot.com/2010/07/atypical-prion-proteins-and-ibnc-in.html
IBNC
"All of the 15 cattle tested showed that the brains had abnormally accumulated prion protein."
Saturday, February 28, 2009
NEW RESULTS ON IDIOPATHIC BRAINSTEM NEURONAL CHROMATOLYSIS "All of the 15 cattle tested showed that the brains had abnormally accumulated PrP" 2009
SEAC 102/2
http://bse-atypical.blogspot.com/2009/02/new-results-on-idiopathic-brainstem.html
Thursday, June 23, 2011
Experimental H-type bovine spongiform encephalopathy characterized by plaques and glial- and stellate-type prion protein deposits
http://transmissiblespongiformencephalopathy.blogspot.com/2011/06/experimental-h-type-bovine-spongiform.html
WHAT ABOUT those old studies at Mission, Texas, where USA scrapie was transmitted to USA cattle, but the results was not c-BSE. IT was a different TSE.
WHAT ABOUT atypical Nor-98 Scrapie in the USA, and TSE there from to other species ???
The key word here is diverse. What does diverse mean?
If USA scrapie transmitted to USA bovine does not produce pathology as the UK c-BSE, then why would CJD from there look like UK vCJD?"
SEE FULL TEXT ;
http://www.promedmail.org/pls/apex/f?p=2400:1001:568933508083034::NO::F2400_P1001_BACK_PAGE,F2400_P1001_PUB_MAIL_ID:1000,82101
.57 The experiment which might have determined whether BSE and scrapie were caused by the same agent (ie, the feeding of natural scrapie to cattle) was never undertaken in the UK. It was, however, performed in the USA in 1979, when it was shown that cattle inoculated with the scrapie agent endemic in the flock of Suffolk sheep at the United States Department of Agriculture in Mission, Texas, developed a TSE quite unlike BSE. 32 The findings of the initial transmission, though not of the clinical or neurohistological examination, were communicated in October 1988 to Dr Watson, Director of the CVL, following a visit by Dr Wrathall, one of the project leaders in the Pathology Department of the CVL, to the United States Department of Agriculture. 33 The results were not published at this point, since the attempted transmission to mice from the experimental cow brain had been inconclusive. The results of the clinical and histological differences between scrapie-affected sheep and cattle were published in 1995. Similar studies in which cattle were inoculated intracerebrally with scrapie inocula derived from a number of scrapie-affected sheep of different breeds and from different States, were carried out at the US National Animal Disease Centre. 34 The results, published in 1994, showed that this source of scrapie agent, though pathogenic for cattle, did not produce the same clinical signs of brain lesions characteristic of BSE.
32 Clark, W., Hourrigan, J. and Hadlow, W. (1995) Encephalopathy in Cattle Experimentally Infected with the Scrapie Agent, American Journal of Veterinary Research, 56, 606-12
33 YB88/10.00/1.1
http://web.archive.org/web/20040823105233/www.bseinquiry.gov.uk/files/yb/1988/10/00001001.pdf
Thursday, June 23, 2011
Experimental H-type bovine spongiform encephalopathy characterized by plaques and glial- and stellate-type prion protein deposits
http://transmissiblespongiformencephalopathy.blogspot.com/2011/06/experimental-h-type-bovine-spongiform.html
Thursday, July 21, 2011
A Second Case of Gerstmann-Sträussler-Scheinker Disease Linked to the G131V Mutation in the Prion Protein Gene in a Dutch Patient Journal of Neuropathology & Experimental Neurology:
August 2011 - Volume 70 - Issue 8 - pp 698-702
http://transmissiblespongiformencephalopathy.blogspot.com/2011/07/second-case-of-gerstmann-straussler.html
Wednesday, June 15, 2011
Galveston, Texas - Isle port moves through thousands of heifers headed to Russia, none from Texas, Alabama, or Washington, due to BSE risk factor
http://transmissiblespongiformencephalopathy.blogspot.com/2011/06/galveston-texas-isle-port-moves-through.html
Monday, June 20, 2011 2011
Annual Conference of the National Institute for Animal Agriculture ATYPICAL NOR-98 LIKE SCRAPIE UPDATE USA
http://nor-98.blogspot.com/2011/06/2011-annual-conference-of-national.html
Thursday, July 14, 2011
Histopathological Studies of “CH1641-Like” Scrapie Sources Versus Classical Scrapie and BSE Transmitted to Ovine Transgenic Mice (TgOvPrP4)
http://transmissiblespongiformencephalopathy.blogspot.com/2011/07/histopathological-studies-of-ch1641.html
Thursday, June 2, 2011
USDA scrapie report for April 2011 NEW ATYPICAL NOR-98 SCRAPIE CASES Pennsylvania AND California
http://nor-98.blogspot.com/2011/06/usda-scrapie-report-for-april-2011-new.html
BSE: TIME TO TAKE H.B. PARRY SERIOUSLY
If the scrapie agent is generated from ovine DNA and thence causes disease in other species, then perhaps, bearing in mind the possible role of scrapie in CJD of humans (Davinpour et al, 1985), scrapie and not BSE should be the notifiable disease. ...
http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk/files/yb/1988/06/08004001.pdf
Monday, June 27, 2011
Zoonotic Potential of CWD: Experimental Transmissions to Non-Human Primates
http://chronic-wasting-disease.blogspot.com/2011/06/zoonotic-potential-of-cwd-experimental.html
UPDATED DATA ON 2ND CWD STRAIN
Wednesday, September 08, 2010
CWD PRION CONGRESS SEPTEMBER 8-11 2010
http://chronic-wasting-disease.blogspot.com/2010/09/cwd-prion-2010.html
Wednesday, January 5, 2011
ENLARGING SPECTRUM OF PRION-LIKE DISEASES Prusiner Colby et al 2011
Prions
David W. Colby1,* and Stanley B. Prusiner1,2
http://betaamyloidcjd.blogspot.com/2011/01/enlarging-spectrum-of-prion-like.html
2006
USA sporadic CJD cases rising ;
There is a growing number of human CJD cases, and they were presented last week in San Francisco by Luigi Gambatti(?) from his CJD surveillance collection.
He estimates that it may be up to 14 or 15 persons which display selectively SPRPSC and practically no detected RPRPSC proteins.
http://www.fda.gov/ohrms/dockets/ac/06/transcripts/1006-4240t1.htm
http://www.fda.gov/ohrms/dockets/ac/06/transcripts/2006-4240t1.pdf
2008
The statistical incidence of CJD cases in the United States has been revised to reflect that there is one case per 9000 in adults age 55 and older. Eighty-five percent of the cases are sporadic, meaning there is no known cause at present.
http://www.cjdfoundation.org/fact.html
CJD USA RISING, with UNKNOWN PHENOTYPE ;
5 Includes 41 cases in which the diagnosis is pending, and 17 inconclusive cases;
*** 6 Includes 46 cases with type determination pending in which the diagnosis of vCJD has been excluded.
http://www.cjdsurveillance.com/pdf/case-table.pdf
Saturday, January 2, 2010
Human Prion Diseases in the United States January 1, 2010 ***FINAL***
http://prionunitusaupdate2008.blogspot.com/2010/01/human-prion-diseases-in-united-states.html
Manuscript Draft Manuscript Number: Title: HUMAN and ANIMAL TSE Classifications i.e. mad cow disease and the UKBSEnvCJD only theory Article Type: Personal View Corresponding Author: Mr. Terry S. Singeltary, Corresponding Author's Institution: na First Author: Terry S Singeltary, none Order of Authors: Terry S Singeltary, none; Terry S. Singeltary Abstract: TSEs have been rampant in the USA for decades in many species, and they all have been rendered and fed back to animals for human/animal consumption. I propose that the current diagnostic criteria for human TSEs only enhances and helps the spreading of human TSE from the continued belief of the UKBSEnvCJD only theory in 2007.
http://www.regulations.gov/fdmspublic/ContentViewer?objectId=090000648027c28e&disposition=attachment&contentType=pdf
my comments to PLosone here ;
http://www.plosone.org/annotation/listThread.action?inReplyTo=info%3Adoi%2F10.1371%2Fannotation%2F04ce2b24-613d-46e6-9802-4131e2bfa6fd&root=info%3Adoi%2F10.1371%2Fannotation%2F04ce2b24-613d-46e6-9802-4131e2bfa6fd
Thursday, August 12, 2010
Seven main threats for the future linked to prions First threat The TSE road map defining the evolution of European policy for protection against prion diseases is based on a certain numbers of hypotheses some of which may turn out to be erroneous. In particular, a form of BSE (called atypical Bovine Spongiform Encephalopathy), recently identified by systematic testing in aged cattle without clinical signs, may be the origin of classical BSE and thus potentially constitute a reservoir, which may be impossible to eradicate if a sporadic origin is confirmed.
***Also, a link is suspected between atypical BSE and some apparently sporadic cases of Creutzfeldt-Jakob disease in humans. These atypical BSE cases constitute an unforeseen first threat that could sharply modify the European approach to prion diseases.
Second threat
snip...
http://www.neuroprion.org/en/np-neuroprion.html
WITH more and more atypical Transmissible Spongiform Encephalopathy cases showing up in more and more species here in North America, and the enormous monumental amount of banned mad cow protein in commerce since the infamous partial and voluntary mad cow feed ban inked on paper, with tons and tons crossing back and forth between the USA, Canada, and Mexico, it just does not surprise me of all these "PENDING CLASSIFICATIONS" of human TSE in Canada, and the USA. UK c-BSE transmitted to humans became nvCJD. WE now have atypical strains of BSE in cattle. Mission Texas experiments long ago showed that transmitted USA sheep scrapie to USA bovine, produced a TSE much different than the UK typical c-BSE. SO why would human TSE in the USA look like UK human TSE ? The corruption is mind boggling. The UK saw a suspicious TSE in humans, and science linked it to cattle. North America is awash with human and animal TSE, CJD is rising in young and old, with the same pathology and same symptoms, and none of it is related to the other. isn't that nice. who, what, bestowed such miracles upon North America $ Archive Number 20100405.1091 Published Date 05-APR-2010 Subject PRO/AH/EDR> Prion disease update 1010 (04)
snip...
[Terry S. Singeltary Sr. has added the following comment:
"According to the World Health Organisation, the future public health threat of vCJD in the UK and Europe and potentially the rest of the world is of concern and currently unquantifiable. However, the possibility of a significant and geographically diverse vCJD epidemic occurring over the next few decades cannot be dismissed.
The key word here is diverse. What does diverse mean? If USA scrapie transmitted to USA bovine does not produce pathology as the UK c-BSE, then why would CJD from there look like UK vCJD?"
http://www.promedmail.org/pls/apex/f?p=2400:1001:568933508083034::NO::F2400_P1001_BACK_PAGE,F2400_P1001_PUB_MAIL_ID:1000,82101
CANADA CJD UPDATE 2011
CJD Deaths Reported by CJDSS1, 1994-20112 As of January 31, 2011
3. Final classification of 49 cases from 2009, 2010, 2011 is pending.
snip...
http://www.phac-aspc.gc.ca/hcai-iamss/cjd-mcj/cjdss-ssmcj/pdf/stats_0111-eng.pdf
USA 2011
USA
National Prion Disease Pathology Surveillance Center
Cases Examined1
(November 1, 2010)
Year Total Referrals2 Prion Disease Sporadic Familial Iatrogenic vCJD
1996 & earlier 51 33 28 5 0 0
1997 114 68 59 9 0 0
1998 87 51 43 7 1 0
1999 121 73 65 8 0 0
2000 146 103 89 14 0 0
2001 209 119 109 10 0 0
2002 248 149 125 22 2 0
2003 274 176 137 39 0 0
2004 325 186 164 21 0 13
2005 344 194 157 36 1 0
2006 383 197 166 29 0 24
2007 377 214 187 27 0 0
2008 394 231 205 25 0 0
2009 425 258 215 43 0 0
2010 333 213 158 33 0 0
TOTAL 38315 22656 1907 328 4 3
1 Listed based on the year of death or, if not available, on year of referral;
2 Cases with suspected prion disease for which brain tissue and/or blood (in familial cases) were submitted;
3 Disease acquired in the United Kingdom;
4 Disease was acquired in the United Kingdom in one case and in Saudi Arabia in the other case;
5 Includes 18 cases in which the diagnosis is pending, and 18 inconclusive cases;
6 Includes 23 (22 from 2010) cases with type determination pending in which the diagnosis of vCJD has been excluded.
http://www.cjdsurveillance.com/pdf/case-table.pdf
Please notice where sporadic CJD cases in 1996 went from 28 cases, to 215 cases in 2009, the highest recorded year to date. sporadic CJD is on a steady rise, and has been since 1996.
I also urge you to again notice these disturbing factors in lines 5 and 6 ;
5 Includes 18 cases in which the diagnosis is pending, and 18 inconclusive cases;
6 Includes 23 (22 from 2010) cases with type determination pending in which the diagnosis of vCJD has been excluded.
========end=====tss=====2011
Monday, August 9, 2010
National Prion Disease Pathology Surveillance Center Cases Examined (July 31, 2010)
(please watch and listen to the video and the scientist speaking about atypical BSE and sporadic CJD and listen to Professor Aguzzi)
http://prionunitusaupdate2008.blogspot.com/2010/08/national-prion-disease-pathology.html
Saturday, March 5, 2011
MAD COW ATYPICAL CJD PRION TSE CASES WITH CLASSIFICATIONS PENDING ON THE RISE IN NORTH AMERICA
http://transmissiblespongiformencephalopathy.blogspot.com/2011/03/mad-cow-atypical-cjd-prion-tse-cases.html
Thursday, August 4, 2011
Terry Singeltary Sr. on the Creutzfeldt-Jakob Disease Public Health Crisis, Date aired: 27 Jun 2011
http://transmissiblespongiformencephalopathy.blogspot.com/2011/08/terry-singeltary-sr-on-creutzfeldt.html
TSS
