Biochemical typing of pathological prion protein in aging cattle with BSE
Virology Journal 2009, 6:64 doi:10.1186/1743-422X-6-64 Seraina Tester (mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000056/!x-usc:mailto:firstname.lastname@example.org) Valerie Juillerat (mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000056/!x-usc:mailto:email@example.com) Marcus G Doherr (mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000056/!x-usc:mailto:firstname.lastname@example.org) Bianca Haase (mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000056/!x-usc:mailto:email@example.com) Miroslaw Polak (mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000056/!x-usc:mailto:firstname.lastname@example.org) Felix Ehrensperger (mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000056/!x-usc:mailto:email@example.com) Tosso Leeb (mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000056/!x-usc:mailto:firstname.lastname@example.org) Andreas Zurbriggen (mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000056/!x-usc:mailto:email@example.com) Torsten Seuberlich (mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000056/!x-usc:mailto:firstname.lastname@example.org) ISSN 1743-422X Article type Research Submission date 23 March 2009 Acceptance date 26 May 2009 Publication date 26 May 2009 Article URL http://www.virologyj.com/content/6/1/64 This peer-reviewed article was published immediately upon acceptance. It can be downloaded, printed and distributed freely for any purposes (see copyright notice below). Articles in Virology Journal are listed in PubMed and archived at PubMed Central. For information about publishing your research in Virology Journal or any BioMed Central journal, go to http://www.virologyj.com/info/instructions/ For information about other BioMed Central publications go to http://www.biomedcentral.com/ Virology Journal © 2009 Tester et al. , licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 1
Biochemical typing of pathological prion protein in aging cattle with BSE
Seraina Tester1, Valerie Juillerat1, Marcus G. Doherr1, Bianca Haase2, Miroslaw Polak3, Felix Ehrensperger4, Tosso Leeb2, Andreas Zurbriggen1 and Torsten Seuberlich1* 1 NeuroCenter, Reference Laboratory for TSE in animals, Department of Clinical Research and Veterinary Public Health, Vetsuisse Faculty, University of Berne, Switzerland 2 Institute of Genetics, Vetsuisse Faculty, University of Berne, Switzerland 3 National Veterinary Research Institute, Pulawy, Poland 4 Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zürich, Switzerland ST: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000056/!x-usc:mailto:email@example.com VJ: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000056/!x-usc:mailto:firstname.lastname@example.org MGD: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000056/!x-usc:mailto:email@example.com BH: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000056/!x-usc:mailto:firstname.lastname@example.org MP: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000056/!x-usc:mailto:email@example.com FE: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000056/!x-usc:mailto:firstname.lastname@example.org TL: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000056/!x-usc:mailto:email@example.com AZ: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000056/!x-usc:mailto:firstname.lastname@example.org *Corresponding author: Dr. med. vet. Torsten Seuberlich NeuroCenter - Reference Laboratory for TSE in animals Department of Clinical Research and VPH Vetsuisse Faculty University of Berne Bremgartenstrasse 109a CH- 3001 Berne Switzerland Email: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000056/!x-usc:mailto:email@example.com Phone: +41 31 631 2206 Fax: +41 31 631 2538 2
The broad enforcement of active surveillance for bovine spongiform encephalopathy (BSE) in 2000 led to the discovery of previously unnoticed, atypical BSE phenotypes in aged cattle that differed from classical BSE (C-type) in biochemical properties of the pathological prion protein. Depending on the molecular mass and the degree of glycosylation of its proteinase K resistant core fragment (PrPres), mainly determined in samples derived from the medulla oblongata, these atypical cases are currently classified into low (L)-type or high (H)-type BSE. In the present study we address the question to what extent such atypical BSE cases are part of the BSE epidemic in Switzerland.
To this end we analyzed the biochemical PrPres type by Western blot in a total of 33 BSE cases in cattle with a minimum age of eight years, targeting up to ten different brain regions. Our work confirmed H-type BSE in a zebu but classified all other cases as C-type BSE; indicating a very low incidence of H- and L-type BSE in Switzerland. It was documented for the first time that the biochemical PrPres type was consistent across different brain regions of aging animals with C-type and H-type BSE, i.e. independent of the neuroanatomical structure investigated.
Taken together this study provides further characteristics of the BSE epidemic in Switzerland and generates new baseline data for the definition of C- and H-type BSE phenotypes, thereby underpinning the notion that they indeed represent distinct prion disease entities.
Taken together these results indicate that the prevalence of H- and L-type BSE in Switzerland remains under the detection limit of the Swiss active surveillance program. However one H-type BSE case was identified by passive BSE surveillance and proves in principle the capacity to identify such cases in the population. Hence, the overall prevalence of atypical BSE in Switzerland appears very low and similar to what has been reported from other countries. It has been speculated and strengthened by experimental data [53,54] that atypical BSE once recycled in the cattle population was the origin of the worldwide BSE epidemic in the last 20 years. If this holds true and such cases occur spontaneously in the population, then BSE might never be completely eradicated. Furthermore, in these circumstances, it would be hazardous to relieve certain disease control measures, including the total prohibition of MBM in ruminant feed.
O.K., let me get this straight, we have typical, U.K. c-BSE, we have now a spontaneous atypical h-BSE and l-BSE, of which they are now just calling an 'old cow disease', which happens spontaneously without any route or source, just happens.
OH, and then we have the new/old ibncBSE, of which is just another 'old cow prion disease', another one of those spontaneous events $$$
IT SEEMS there is a pattern here to make all Transmissible Spongiform Encephalopathies a spontaneous event, even though there is no such evidence what so ever.
WITH all the sub-types of TSE showing up now in the Scrapie, BSE, CWD, (all of which has been rendered and fed back to livestock producing animals for human and animal feed), and even in humans i.e. CJD, there is no way, they know for a fact that all are of a spontaneous, sporadic event, that just happened due to a twisted up protein that folded the wrong way by itself, from no route and no source. they do NOT know if any of these atypical TSE are of a spontaneous old cows prion disease or not, but yet they preach it like it's the gospel $$$
I don't believe them today, and i will never believe that 85%+ of all human sporadic CJD, just happens without any route and source from anything. ...
kind regards, terry
Absence of spontaneous disease and comparative prion susceptibility of transgenic mice expressing mutant human prion proteins
Emmanuel A. Asante, Ian Gowland, Andrew Grimshaw, Jacqueline M. Linehan, Michelle Smidak, Richard Houghton, Olufunmilayo Osiguwa, Andrew Tomlinson, Susan Joiner, Sebastian Brandner, Jonathan D. F. Wadsworth and John Collinge Correspondence John Collinge mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000056/!x-usc:mailto:firstname.lastname@example.org MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK Received 15 October 2008 Accepted 2 December 2008
Approximately 15% of human prion disease is associated with autosomal-dominant pathogenic mutations in the prion protein (PrP) gene. Previous attempts to model these diseases in mice have expressed human PrP mutations in murine PrP, but this may have different structural consequences. Here, we describe transgenic mice expressing human PrP with P102L or E200K mutations and methionine (M) at the polymorphic residue 129. Although no spontaneous disease developed in aged animals, these mice were readily susceptible to prion infection from patients with the homotypic pathogenic mutation. However, while variant Creutzfeldt-Jakob disease (CJD) prions transmitted infection efficiently to both lines of mice, markedly different susceptibilities to classical (sporadic and iatrogenic) CJD prions were observed. Prions from E200K and classical CJD M129 homozygous patients, transmitted disease with equivalent efficiencies and short incubation periods in human PrP 200K, 129M transgenic mice. However, mismatch at residue 129 between inoculum and host dramatically increased the incubation period. In human PrP 102L, 129M transgenic mice, short disease incubation periods were only observed with transmissions of prions from P102L patients, whereas classical CJD prions showed prolonged and variable incubation periods irrespective of the codon 129 genotype. Analysis of diseaserelated PrP (PrPSc) showed marked alteration in the PrPSc glycoform ratio propagated after transmission of classical CJD prions, consistent with the PrP point mutations directly influencing PrPSc assembly. These data indicate that P102L or E200K mutations of human PrP have differing effects on prion propagation that depend upon prion strain type and can be significantly influenced by mismatch at the polymorphic residue 129.
Transgenic mice expressing high levels of mouse PrP 101L (equivalent to 102L in human PrP) spontaneously developed neurological dysfunction at 166 days of age (Hsiao et al., 1990). PrPSc levels were low or undetectable, and brain extracts from affected mice did not transmit CNS degeneration to wild-type mice, but transmission to hamsters and Tg(GSSPrP)196 mice, expressing lower levels of the same mutant transgene product, was reported (Hsiao et al., 1994; Telling et al., 1996a). These Tg(GSSPrP)196 mice have subsequently been reported to develop spontaneous disease at advanced age (Tremblay et al., 2004; Nazor et al., 2005). It therefore remains debateable as to whether prions had been generated in these transgenic mice or this simply represents acceleration of a spontaneous neurodegenerative disease already poised to occur in these mice (Nazor et al., 2005). Others generated transgenic mice expressing endogenous levels of mouse PrP 101L by the gene knock-in approach (Manson et al., 1999). These mice did not develop spontaneous neurodegeneration but were reported to show greater susceptibility to human P102L prions than wildtype mice (Barron et al., 2001).
However, we consider it essential to study this and other human pathogenic mutations in human PrP, rather than in mouse PrP where the mutation may have different structural consequences. With respect to such models it is important to demonstrate that human PrP is functionally active and can participate in prion propagation and pathogenesis in mouse cells. Human PrP can rescue a PrP null phenotype in mice (Whittington et al., 1995), confirming it is functionally active and human prions can replicate in transgenic mice expressing only human PrP, which develop spongiform neurodegeneration (Collinge et al., 1995).
snip...see full text ;
******  Correction Date: Tue 5 Sep 2006 From: "Terry S Singeltary Sr" <mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000056/!x-usc:mailto:email@example.com>
Characterization of atypical BSE in Germany:
[In the Moderator's comment accompanying the abstract of the paper entitled "Atypical BSE in Germany-Proof of transmissibility and biochemical characterization'" by A Buschmannaet et al, (see part  of CJD (new var.) update 2006 (09) 20060904.2519) it was wrongly implied that Terry S Singeltary Sr endorsed the conclusions of the paper, whereas his comments were intended merely to highlight the conclusions of the paper. Namely that the atypical cases suggested the possible existence of sporadic BSE cases in bovines and perhaps the BSE epidemic in the UK could have also been initiated by an intraspecies transmission from a sporadic BSE case. I apologize for inadvertently misrepresenting Terry's views. - Mod.CP]
Terry S Singeltary Sr has written the following. "In fact I disagree with the spontaneous/sporadic BSE/TSE theory, IF this is what the authors of this paper meant by 'sporadic BSE' to mean. For one thing, it has never been proven. IF atypical BSE i.e. BASE is so similar to some sporadic CJDs, then how did they all of a sudden become spontaneous? Could it not be so simple as an atypical BSE i.e. BASE was transmitted the same way most of all of the other BSE cattle were i.e. feed of just an atypical source, thus causing atypical strain? Why would these animals not develop an atypical BSE i.e. BASE from the same oral route? WHAT about an atypical strain mutating to become infectious via a lateral or horizontal mode in the bovine, as with CWD and scrapie? Also, please explain to me how a distinct synthetic prion, of a strain that is supposedly unlike any other we have ever seen, how can this explain 6 different documented phenotypes of sporadic CJD to date?
It's like trying to explain away all the 6 phenotypes of sporadic CJD with the spontaneous theory, it's just not scientific. OR, if you render an atypical TSE of what ever phenotype, in what ever species, of the atypical strain and feed it to another whatever species, nothing happens x 1 x 2 x 3 x 4 etc passage? This all has been proven?
Please show me these transmission studies? What Prusiner and Soto produced in vitro did not look like any natural field TSE, and as far as this in vitro TSE being infectious, well this was questionable too. If this was the case, then why does CWD not spontaneously happen in geographical areas where it has never been documented, OR with scrapie, as in scrapie free New Zealand? If TSE were to arise spontaneously, I don't see how the scientific arena can dictate which animal TSE can arise spontaneously, and which ones cannot, without any scientific evidence to support this to date, and by even suggesting this in this study, was not scientific. The words sporadic and spontaneous are very confusing in the world literature of human and animal TSE and, in my opinion, should not be used as terminology of any TSE."
-- Terry S Singeltary Sr <mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000056/!x-usc:mailto:firstname.lastname@example.org>
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
Sunday, May 17, 2009
De Novo Generation of Infectious Prions In Vitro Produces a New Disease Phenotype
Monday, May 11, 2009
Rare BSE mutation raises concerns over risks to public health
Sunday, April 12, 2009
BSE MAD COW TESTING USA 2009 FIGURES Month Number of Tests
Feb 2009 -- 1,891
Jan 2009 -- 4,620
SEE FULL TEXT ;
Monday, May 4, 2009
Back to the Past With New TSE Testing Agricultural Research/May-June 2009
Sunday, May 10, 2009
Identification and characterization of bovine spongiform encephalopathy cases diagnosed and NOT diagnosed in the United States
Friday, May 29, 2009
Characterization of a U.S. Sheep Scrapie Isolate with Short Incubation Time
Friday, May 29, 2009
Seven Deer Test Positive for Chronic Wasting Disease During 2009 Spring Collections in Hampshire County, West Virginia
O.K. confusious asks, IF all these new atypical BSEs i.e. new strains of mad cow disease is just an 'OLD COW PRION DISEASE', why then can not the 'old human prion disease' such as the sporadic CJD, be from an 'old cow prion disease', same as the nvCJD 'young people mad cow disease' (which also happens in 74 year old), but why cannot the 'old cow prion diseases', i.e. l-BSE, h-BSE, and ibncBSE, cause the 'old people prion disease', which looks like sporadic CJD. seems that is what some of the pathology is showing ???
OH, that probably makes too much sense, and that the only answer could be that it's all just a happenstance of bad luck and or a spontaneous event, that just happens out of the clear blue sky $$$
IF this is the case, then where are all the SPONTANEOUS BSE CASES OF MAD COW DISEASE IN THE U.S.A., AND WHERE HAVE THEY BEEN BURIED IN THE USA OVER THE LAST 25 YEARS ???
Atypical BSE North America Update February 2009
Sunday, December 28, 2008
MAD COW DISEASE USA DECEMBER 28, 2008 an 8 year review of a failed and flawed policy
Wednesday, August 20, 2008
Bovine Spongiform Encephalopathy Mad Cow Disease typical and atypical strains, was there a cover-up ?
Terry S. Singeltary Sr.
P.O. Box 42
Bacliff, Texas USA 77518