Endogenous Viral Etiology of Prion Diseases
Eradicating transmissible spongiform encephalopathies (TSEs) in farm animals by deleting the endogenous viral gene PRNP is technologically feasible, ethically acceptable, makes sense commercially and, by eliminating the risk for TSE transmission to humans and to domestic and wild animals, it is a sensible public health preventive measure.
Unlike the prion hypothesis, the endogenous TSE virus model is consistent with all current data, it makes evolutionary sense, and it provides solutions to many TSE enigmatic features ([1]; see comment above). Moreover, by explaining the TSE phenomenon, this model opens the door to new therapeutic approaches and it offers a new strategy for eradicating TSEs, such as "mad cow disease" [bovine spongiform encephalopathy (BSE)] in cattle, and scrapie in sheep and goats (see comments above). This strategy consists of deleting the endogenous viral gene PRNP from reproductive stocks. As discussed next, using this approach to eradicate TSEs is technologically feasible, ethically acceptable, and makes sense commercially. More importantly, though, by eradicating the TSEs in farm animals, this program would abolish the transmission of these fatal diseases to humans and to other domesticated and wild animals, which would be an extraordinary public health accomplishment.
The devastating BSE epidemic in the United Kingdom (UK), and the strong evidence that BSE was transmitted to humans causing the variant Creutzfeldt-Jacob disease (vCJD) [2;3] have profoundly changed the guidelines for animal farming and associated industries, as well as for public health [4;5]. One of the major long-term measures to prevent future TSE epidemics was the implementation of large-scale selective breeding programmes that would reduce the risk for developing TSE (reviewed in [6-9]). This approach was based on the findings that certain alleles (i.e. "mutations") of a gene called PRNP, which was first identified as a TSE-associated genetic locus in mice and sheep [10] and later as a TSE specific gene in mice [11] and other vertebrates (reviewed in [12]), are associated with a reduced risk for developing TSE (reviewed in [6-9]).
The rationale, the strategies, and the early results of these selective breeding programmes, particularly as applied to sheep, have been discussed at length in numerous publications (reviewed in [6-9]). These programmes are remarkable examples of successfully integrating diverse scientific, political, social, and economical interests into an impressive effort to control one of the most frightening diseases of our time. However, as discussed next, when the scientific foundation and the understanding of a disease is inadequate, or even misleading, the effort is undermined.
The prion concept, which has been the working hypothesis in the TSE field for more than two decades [13], was developed under the umbrella of the misleading dogma of viruses as virus particles, and it was founded on a poor understanding of the biochemistry and dynamics of protein folding and the relationship between genotype and phenotype ([1;14]; see comments above). As discussed in the paper and in the comments above, by defining the 'prion protein' (i.e. PrP-Sc) as a novel type of self-replicating pathogen independent of its gene PRNP, the prion concept has not only tarnished our scientific intellect and academic integrity but has negatively affected the progress in TSE and related fields, including finding a cure or developing strategies for eradicating this group of fatal diseases and, possibly, for understanding other related human diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington 's disease (HD).
A case in point is the role this flawed concept has played in the implementation of the selective breeding programmes for reducing the risk for TSE, instead of, or in parallel with, a superior alternative approach consisting of inactivating or deleting the PRNP gene. This alternative approach is superior because unlike the selective breeding programmes, which only reduce the risk to some, but not necessarily to all forms of TSEs, deleting or inactivating the PRNP gene would completely eradicate all forms of TSEs, and more importantly would eliminate TSE transmission to humans and other animals. There is, however, a big problem with deleting or inactivating this gene, a problem associated with the misleading prion hypothesis. In order to promote and sustain its novelty that the TSEs do not have a viral etiology, the prion hypothesis has trumpeted for decades the false statement that PRNP is a normal cellular gene [11;13]. And, as it is well known, experimentally tampering with or modifying the genes of livestock is not ethically acceptable [15].
However, as first hypothesized twenty five years ago [16], and since then proven correct beyond any reasonable doubt (see paper and comments above), the PRNP is an endogenous viral gene and, therefore, it would make sense to inactivate or delete it from breeding livestock, such as cows, sheep and goats, which are susceptible to developing TSE. Paradoxically, even within the current scientific establishment, it is fully accepted that some members of the PRNP gene family (e.g. PRNT) have a viral nature [12;17]. However, accepting that TSEs have a viral etiology would invalidate the prion hypothesis, which has directed the thinking and the research in the TSE and related fields for more than two decades, and that might be a sensitive issue. Clearly, however, TSEs have endogenous viral etiology, and it would make sense to abandon the misleading prion hypothesis and liberate the TSE and associated fields from its obvious limitations.
The selective breeding approach has been challenging from the beginning because after more than two decades of very intense research involving dozens of laboratories and hundreds of researchers, the primary function of PRNP is still not known (note: although the PRNP gene causes TSE, it is assumed that the primary phenotype conferred by this gene is a non-pathogenic phenotype, and that TSE is just a secondary, 'accidental' phenotype). As discussed in the paper and in the comments above, this lack of progress in figuring out the primary function of PRNP is another pragmatic and costly example of the limitations imposed by the misleading prion hypothesis on the TSE research. On top of not knowing the function of PRNP, and therefore not knowing what phenotype(s) it might control the researchers and breeders were faced with two additional issues, which are inherent to most strong selective breeding programmes, namely: the potential for co-selection of genetically-linked undesirable traits, and a reduction in the genetic diversity of the breeding population. (Note: to address these major concerns, reproductive cells from unselected breeding stock have been stored as an emergency safety measure in case of a need to re-introduce the 'natural' genetic variation). If conducted on a large scale, generating livestock of cows, sheep, and goats with their endogenous viral PRNP inactivated or deleted, which is technologically and commercially feasible, would minimize these legitimate concerns and problems.
Fortunately, it appears that the main biological and performance traits, such as fertility, health and survival, growth rate, carcass composition, or milk production in the selected breeding stock are not negatively affected, at least not in the short term and not to an extent that overrides the potential benefits from reducing the risk for TSE. However, it is important to realize that these results were expected because we have known for two decades that mice and more recently cows and goats that have had their PRNPs deleted or inactivated (commonly referred to as PRNP 'null' animals) are relatively normal [18-20]. The rationale behind this expectation is that, if inactivating or deleting the PRNP gene does not seem to affect whatever 'hidden' phenotype (s) this gene controls, neither would the mutations. Nonetheless, monitoring the biological and performance traits of the animals carrying selected PRNP alleles, or for that matter monitoring PRNP 'null' animals, is necessary because all experimental laboratory findings need to be validated in the field.
Although, unlike the "PRNP null approach", the "PRNP selection approach" reduces the genetic variation in the breeding stocks (again, this is a intrinsic feature of all selective breeding approaches), when it comes to preserving the main biological and performance (i.e. commercial) traits, both approaches appear to work well. However, when it comes to TSE, the two approaches are no longer equivalent. What is important to realize is that the "PRNP selection approach" does not eradicate TSE. It only reduces the risk for developing TSE. And, it might do that only for the "classical forms" of TSEs, not other forms of TSE such as the "atypical forms" that were recently discovered [21-33] In fact, it is possible that this approach might increase the risk for the development and transmission of some of the new forms of TSE. In contrast, the "PRPN null approach" leads to the eradication of all forms of TSEs, and completely abolishes transmission to humans and other domestic or wild animals.
Before concluding this comment, it is relevant to discuss a very important issue that concerning the primary, or "natural," function of the endogenous TSE virus gene PRNP. As discussed at length in the paper and the comments above, the endogenous PRNP viral gene has evolved and has been maintained in vertebrate lineage because it provides a symbiotic, beneficial function to the host and to itself of course, specifically a protective function against other viruses. This is a relatively common phenomenon in virus/host relationships; indeed, many if not most viruses have evolved various mechanisms for protecting the infected cells, and themselves, from other viruses. Apparently, the endogenous PRNP viral gene uses two protective mechanisms, one is protein-based and the other RNA-based (in addition to the genetic, biochemical, structural, and evolutionary evidence, the discovery of the RNA-elements produced by the PRNP gene also points to its viral nature, and once more invalidates the prion hypothesis). The concern here, particularly as it relates to the "PRPN null approach," is that inactivating or deleting this gene might increase susceptibility to some viral infections (note: selection of certain PRNP alleles might have a similar effect, although possibly less severe). Definitely, this is a legitimate concern, but it might be of less relevance for livestock for multiple reasons. First of all, the antiviral protective functions provided by the endogenous TSE virus gene PRNP is only one of the many innate and adaptive immune antiviral mechanisms in these animals. Therefore, the contribution of the PRNP in the survival of these animals might only be relevant for long term evolutionary success in a natural environment and under the laws of natural selection, not under farming conditions. Second, we have developed numerous vaccines and other antiviral preventive measures and therapies, and continue to do so; therefore, the threat for many viral infections has already been reduced to a great extent. Third, in "PRPN null approach," the PRNP does not need to be completely deleted or inactivated. In fact, the RNA-based protective mechanism might be left intact, or even enhanced [if necessary, I can provide a very specific, nucleotide-by-nucleotide (so-to-speak) procedure of how to accomplish this task experimentally]. Also, it might be possible that protein-based protective mechanisms don't need to be completely abolished, but rather modified to such an extent that they will be incompatible with the TSE phenomenon.
In conclusion, the selective breeding programmes currently implemented in UK and many other countries might lead to an increase in resistance to some forms of TSEs, but possibly not all. Moreover, this approach leaves the door open for future TSE epidemics in farm animals and for TSEs transmission to humans and other domestic and wild animals. On the other hand, the "PRPN null approach" eradicates TSE and completely eliminates the risk for transmission. Based alone on the huge commercial losses associated with a TSE epidemic in livestock, as was the case with the BSE epidemic in UK where the losses were in the billions of pounds, it would make more sense to inactivate or delete the pathogenic endogenous viral gene PRNP. Even more, considering the horrendous morbidity and mortality caused by TSE epidemics in both farm animals and humans, implementing the "PRPN null approach" would not only make scientific sense but from a humanitarian, medical and public health perspective it could be regarded as a responsibility.
[I have already made the disclaimer in the paper that "the findings and conclusions in this report are those of the author and do not necessarily represent the views or the opinions of the U.S. Department of Health and Human Services or Centers for Disease Control and Prevention" (see paper); however, it might be appropriate to refresh it in context of this comment].
Endogenous Viral Etiology of Prion Diseases
Claudiu I. Bandea
National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA
October 20, 2009
Claudiu I. Bandea
Transmissible spongiform encephalopathies (TSEs), or prion diseases, are a group of incurable neurodegenerative disorders, including Kuru and Creutzfeldt-Jakob disease in humans, "mad cow"disease in cattle, and scrapie in sheep. This paper presents structural, genetic, and evolutionary evidence supporting an endogenous TSE virus model that integrates the three major traditional views on the nature of TSE pathogens, the conventional virus view, the prion hypothesis, and the virino concept, into a novel conceptual and evolutionary framework. According to this model, the TSE pathogens are symbiotic endogenous viruses that inadvertently produce transmissible viral particles that lack the viral genome and are composed primarily of the viral prion protein (PrP). Production of defective viral particles that contain a partial genome or lack the viral genome entirely is a relatively common event in the life cycle of many viruses. Similar to the normal viral particles, which contain a genome, these defective viral particles can be transmitted to new host cells. Obviously, in the absence of viral genome, these protein-only viral particles cannot establish a productive infection. However, if these viral particles enter a host cell that carries the parental or arelated virus and induce the production of similar protein-only particles, then they would appear as self-replicating, protein-only infectious pathogens if mistakenly taken out from the context of the viral life cycle. This misconception, which is rooted into the current dogma of viruses as viral particles, led to the development of the prion theory. The endogenous TSE virus model is consistent with the TSE data and offers solutions to many enigmatic features associated with TSE, including the function of PrP that, despite more than two decades of TSE research conducted primarily within the framework of the prion hypothesis, is still not known. According to the TSE endogenous virus model,PrP is the protein of an endogenous virus that has co-evolved with their vertebrate hosts by providing a protective function against pathogenic viruses. The evidence for the endogenous TSE virus model and for the antiviral protective function of PrP is strong, and they are fully open to additional experimental testing. The endogenous virus model opens the TSE research field to new interpretations and directions, both in basic research and in associated biomedical and public health fields, and could lead to development of new diagnostic and therapeutic approaches.
http://precedings.nature.com/documents/3887/version/1/files/npre20093887-1.pdfhttp://precedings.nature.com/documents/3887/version/1/htmlEndogenous Viral Etiology of Prion Diseases Claudiu I. Bandea1
Correspondence: cbandea [at] cdc.gov
1.Centers for Disease Control and Prevention, Atlanta, GA 30333 PDF (144.7 KB) .Document Type:Manuscript Date:Received 21 October 2009 18:35 UTC; Posted 23 October 2009
Subjects: Microbiology, Neuroscience, Evolutionary Biology
Tags:TSE Transmissible Spongiform Encephalopathies prions endogenous viruses viral evolution Scrapie
Abstract:
Transmissible spongiform encephalopathies (TSEs), or prion diseases, are a group of incurable neurodegenerative disorders, including Kuru and Creutzfeldt-Jakob disease in humans, “mad cow” disease in cattle, and scrapie in sheep. This paper presents structural, genetic, and evolutionary evidence supporting an endogenous TSE virus model that integrates the three major traditional views on the nature of TSE pathogens, the conventional virus view, the prion hypothesis, and the virino concept, into a novel conceptual and evolutionary framework. According to this model, the TSE pathogens are symbiotic endogenous viruses that inadvertently produce transmissible viral particles that lack the viral genome and are composed primarily of the viral prion protein (PrP). Production of defective viral particles that contain a partial genome or lack the viral genome entirely is a relatively common event in the life cycle of many viruses. Similar to the normal viral particles, which contain a genome, these defective viral particles can be transmitted to new host cells. Obviously, in the absence of viral genome, these protein-only viral particles cannot establish a productive infection. However, if these viral particles enter a host cell that carries the parental or a related virus and induce the production of similar protein-only particles, then they would appear as self-replicating, protein-only infectious pathogens if mistakenly taken out from the context of the viral life cycle. This misconception, which is rooted into the current dogma of viruses as viral particles, led to the development of the prion theory. The endogenous TSE virus model is consistent with the TSE data and offers solutions to many enigmatic features associated with TSE, including the function of PrP that, despite more than two decades of TSE research conducted primarily within the framework of the prion hypothesis, is still not known. According to the TSE endogenous virus model, PrP is the protein of an endogenous virus that has co-evolved with their vertebrate hosts by providing a protective function against pathogenic viruses. The evidence for the endogenous TSE virus model and for the antiviral protective function of PrP is strong, and they are fully open to additional experimental testing. The endogenous virus model opens the TSE research field to new interpretations and directions, both in basic research and in associated biomedical and public health fields, and could lead to development of new diagnostic and therapeutic approaches.
http://precedings.nature.com/documents/3887/version/1Yervand Karapetyan on 30 December 2009 17:53 UTC
While I agree with some of the points made by the author in this paper – e.g. PrP being a capsid protein of a virus – I do not see any evidence of PrP alone being infectious without specific RNA coming form infected brain. None of the papers cited in this manuscript with this regard show that an infectious viral particle of any virus can be assembled from proteins alone without specific viral RNA. One can even substitute viral RNA with synthetic polyA in order to assemble TMV virion like particles (1) , but the infectivity of these complexes has never been demonstrated. While RNA alone, if delivered in enough quantity and protected properly, can be infectious.
The fact that TSE agent does not have coding nucleic acid doesn’t mean it does not have any nucleic acid genome! It can have non coding nucleic acid which will still carry infectivity and strain specific properties just like in the case of viroids and virusoids.
A virusoid (satellite RNA) in order to replicate would need a helper virus to be in every species and cell that is susceptible to infection. Hence the need for latent RNA virus in all TSE susceptible species (you may consider this kind of a virus an ””endogenous”” if you wish).
Interestingly enough Gajdusek proposed such scenario almost four decades ago (2): “These viruses could be associated or satellite viruses which serve to activate or are themselves activated by some helper virus latent in the susceptible host (Gajdusek, 1972).” [Gajdusek, D. C. (1972). Slow virus infections and activation of latent virus infections in aging. Advanc. geront. Res., 4, 201-218.]
References:
1. Schön A, Mundry KW. Coordinated two-disk nucleation, growth and properties, of virus-like particles assembled from tobacco-mosaic-virus capsid protein with poly(A) or oligo(A) of different length. Eur J Biochem. 1984 Apr 2;140(1):119-27.
2. D. Carleton Gajdusek. Spongiform virus encephalopathies doi:10.1136/jcp.s3-6.1.78 1972;s3-6;78-83 J. Clin. Pathol.
see discussions and more comments ;
http://precedings.nature.com/documents/3887/version/1Originally published in Science Express on 31 December 2009
Science 12 February 2010: Vol. 327. no. 5967, pp. 869 - 872 DOI: 10.1126/science.1183218
Reports
Darwinian Evolution of Prions in Cell Culture
Jiali Li,* Shawn Browning,* Sukhvir P. Mahal, Anja M. Oelschlegel, Charles Weissmann
http://www.sciencemag.org/cgi/content/abstract/327/5967/869E-Letters: Submit a response to this article
Published E-Letter responses:
Could Prion Protein Assumptions Engender Misleading Sensational Conclusions?
Igor V. Zaitsev (19 March 2010) The Backwards Evolution of Prions Laura Manuelidis (19 March 2010)
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Could Prion Protein Assumptions Engender Misleading Sensational Conclusions?
19 March 2010
Igor V. Zaitsev Science Department, Borough of Manhattan Community College, The City University of New York, USA
Respond to this E-Letter: Re: Could Prion Protein Assumptions Engender Misleading Sensational Conclusions?
The Report "Darwinian evolution of prions in cell culture" (J. Li et al., 12 February 2010, p. 869, published online 31 December 2009) has caused a sensation on the Web. A group of Florida-based scientists headed by Charles Weissmann have claimed that prion proteins develop drug resistance—that is to say, they are capable of adaptive change, mutation, and evolution. However, in 1997, Laura Manuelidis of the Yale School of Medicine published a Report on the evolution of a strain of Creutzfeldt-Jakob diseases, with a careful analysis of the infection (1), contradicting the conclusion of Weissmann's team.
It is important to ascertain whether Weissmann's team was dealing exclusively with prion proteins, given that it is very difficult to isolate them from nucleic acid contamination. Many scientists, including protein-only hypothesis adherents, identified RNA in similar transplanted inoculants. Stanley Prusiner, the leading advocate for the protein-only hypothesis, confirmed during a 2004 interview with The New York Times that protein-only infection would be conclusively evident if experimental scientists inoculate a synthetic protein to produce transmissible spongiform encephalopathy in animals—in that case, there would be no possibility of inoculum contamination (2).
Prusiner and his research team tried to initiate the disease by inoculating laboratory mice with what he claimed was a synthetic protein. However, Prusiner's team observed only some questionable signs of infection at about 600 or more days after inoculation (3), approximately the life expectancy of laboratory mice. Inoculation with an infected brain homogenate normally leads to an indication of brain pathology in mice brains in about 70 days (4).
The adaptation that Weissmann's team observed is a perfect example of a conventional RNA virus behavior, not of a protein. Therefore, what this group has discovered might be evidence of a virus hypothesis, not a protein-only hypothesis.
Igor V. Zaitsev
Science Department, Borough of Manhattan Community College, The City University of New York, New York, NY 10007-1097, USA.
References
1. L. Manuelidis et al., Science 277, 94 (1997).
2. S. Blakeslee, The New York Times, 30 July 2004.
3. G. Legname et al., Science 305, 673 (2004).
4. C. A. Baker et al., J. Virol. 73, 6 (1999).
The Backwards Evolution of Prions 19 March 2010
Laura Manuelidis, Professor and Head of Neuropathology Yale Medical School, New Haven, CT 06510, USA Respond to this E-Letter: Re: The Backwards Evolution of Prions
J. Li et al. report swainsonine-induced mutation in a single cell type infected with one scrapie strain ("Darwinian evolution of prions in cell culture," Reports, 12 February 2010, p. 869, published online 31 December 2009). They claim that host prion protein encodes the infectious mutant by misfolding (PrPSc). However, they found no evidence of either a new PrPSc or a new mouse strain. Nevertheless, they conclude: "You have exactly the same process of mutation and adaptive change in prions as you see in viruses; adaptability has moved one level down—to prions and protein folding—and it's clear that you do not need nucleic acid (DNA or RNA) for the process of evolution" (1). Many very distinct scrapie and Creutzfelt-Jacob disease (CJD) strains also show the same PrPSc in standard mice (2). Moreover, one can stably change the PrPSc conformation in murine cell cultures for more than 1 year, and only the original strain, not the PrPSc, breeds true (Ref. 15 in the Report). Two CJD strains, as easy to recognize as night and day, retained their unique properties as shown by re-inoculation in mice. The same is true for infected tissues such as spleen. Yet the authors propose that mutant PrPSc strains form outside the brain, regardless of overwhelming evidence to the contrary.
As shown in our Report in Science titled "Evolution of a strain of CJD that induces BSE-like plaques," I certainly agree that transmissible spongiform encephalopathy (TSE) agents can evolve and adapt, or be selected from a quasi-species (3). Moreover, two distinct strains can infect the same cell by superinfection (4). Agent mutation also implicates an intrinsic nucleic acid. The protein of tobacco mosaic virus was similarly declared infectious by ignoring its nucleic acid component. Accumulating evidence has falsified the major claims of infectious PrP [reviewed in (5)]. Yet the authors do not question their prion premise, even though there are substantial data that do not fit, including virus-like structural features and associated nucleic acids that appear to be necessary for infection (6). Moreover, different TSE strains have specific geographic and environmental origins that are inconsistent with spontaneous generation of host-encoded infectivity (2, 7). Clearly, in epidemic bovine spongiform encephalopathy, as in kuru, when you remove the environmental pathogen, the infection (and disease) dramatically falls. Recognition of these facts is critical for public health.
Swainsonine affects many glycosylated cell proteins and it has induced increased PrPSc elsewhere (8), a change opposite to the reduction reported here. Thus, its effects on PrPSc and scrapie strains are variable. The inherent genetic instability of the tumor cells used is also problematic. The extraordinary stability of TSE agents contrasts with a proposed very high mutation rate that appears to be based on cell doublings rather than agent titers. More critically, agent virulence is defined by many factors and realities that underscore host responses to an evasive, exogenous pathogen (9). Widely accepted paradigm-shifting features of the prion concept have now spread to a whole class of neurodegenerative proteins (10).
Laura Manuelidis
Yale Medical School, New Haven, CT 06510, USA.
References
1. C. Weissmann, at http://news.bbc.co.uk/2/hi/health/8435320.stm.
2. L. Manuelidis, T. Chakrabarty, K. Miyazawa, N.-A. Nduom, K. Emerling, Proc. Natl. Acad. Sci. U.S.A. 106, 13529 (2009).
3. L. Manuelidis, W. Fritch, Y.-G. Xi, Science 277, 94 (1997).
4. N. Nishida, S. Katamine, L. Manuelidis, Science 310, 493 (2005).
5. L. Manuelidis, J. Cell Biochem. 100, 897 (2007).
6. S. Simoneau, et al., Natureprecedings (2009); http://precedings.nature.com/documents/3344/version/1.
7. N. Hunter, D. Cairns, J. Gen. Virol. 79, 2079 (1998).
8. K. F. Winklhofer, U. Heller, A. Reintjes, J. Tatzelt, Traffic 4, 313 (2003).
9. L. Manuelidis, Virulence (2009); www.landesbioscience.com/journals/virulence/article/10822.
10. G. Miller, Science 326, 1337 (2009).
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Science. ISSN 0036-8075 (print), 1095-9203 (online)
http://www.sciencemag.org/cgi/eletters/327/5967/869Science 4 July 1997: Vol. 277. no. 5322, pp. 94 - 98 DOI: 10.1126/science.277.5322.94 Prev Table of Contents Next
Reports
Evolution of a Strain of CJD That Induces BSE-Like Plaques
Laura Manuelidis, * William Fritch, You-Gen Xi
Bovine spongiform encephalopathy (BSE) has become a public health issue because a recently evolved BSE agent has infected people, yielding an unusual form of Creutzfeld-Jakob disease (CJD). A new CJD agent that provokes similar amyloid plaques and cerebellar pathology was serially propagated. First-passage rats showed obvious clinical signs and activated microglia but had negligible PrP-res (the more protease-resistant form of host PrP) or cerebellar lesions. Microglia and astrocytes may participate in strain selection because the agent evolved, stabilized, and reproducibly provoked BSE-like disease in subsequent passages. Early vacuolar change involving activated microglia and astrocytes preceded significant PrP-res accumulation by more than 50 days. These studies reveal several inflammatory host reactions to an exogenous agent.
Section of Neuropathology, Yale Medical School, 310 Cedar Street, New Haven, CT 06510, USA. * To whom correspondence should be addressed. E-mail: laura.manuelidis@yale.edu
http://www.sciencemag.org/cgi/content/abstract/277/5322/94http://www.sciencemag.org/cgi/content/full/277/5322/94Prospect A 25 nm virion is the likely cause of transmissible spongiform encephalopathies
Laura ManuelidisArticle first published online: 16 OCT 2006
DOI: 10.1002/jcb.21090
http://onlinelibrary.wiley.com/doi/10.1002/jcb.21090/abstract;jsessionid=4C517EA57A70B99693DBC6DD1A71BD8E.d02t02Laura Manuelidis
Professor & Head of Neuropathology Department of Surgery and Faculty of Neurosciences & Virology B.A. Sarah Lawrence College M.D. Yale Medical School
Contact: Tel: 203-785-4442 Email: laura.manuelidis@yale.edu
current research
http://info.med.yale.edu/neurosci/faculty/manuelidis_main.htmlhttp://www.yalesurgery.org/neuropathology/research/index.aspxThe backwards evolution of the prion concept
http://www.yalesurgery.org/neuropathology/research/prion.aspxPub-Med
http://www.ncbi.nlm.nih.gov/pubmed?term=Manuelidis+L.%5Bau%5DPrion Diseases: No Accomplice Needed
by Jennifer Couzin-Frankel on January 28, 2010 12:00 AM
http://news.sciencemag.org/sciencenow/2010/01/28-03.htmlMonday, August 9, 2010
Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein or just more Prionbaloney ?
http://prionunitusaupdate2008.blogspot.com/2010/08/variably-protease-sensitive-prionopathy.htmlSaturday, August 14, 2010
BSE Case Associated with Prion Protein Gene Mutation (g-h-BSEalabama) and VPSPr PRIONPATHY
http://prionpathy.blogspot.com/2010/08/bse-case-associated-with-prion-protein.htmlWednesday, July 28, 2010
re-Freedom of Information Act Project Number 3625-32000-086-05, Study of Atypical BSE UPDATE July 28, 2010
http://bse-atypical.blogspot.com/2010/07/re-freedom-of-information-act-project.htmlTuesday, July 27, 2010
Spontaneous generation of mammalian prions
http://madcowspontaneousnot.blogspot.com/2010/07/spontaneous-generation-of-mammalian.htmlP.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.pdfWednesday, August 11, 2010
REPORT ON THE INVESTIGATION OF THE SIXTEENTH CASE OF BOVINE SPONGIFORM ENCEPHALOPATHY (BSE) IN CANADA
http://bse-atypical.blogspot.com/2010/08/report-on-investigation-of-sixteenth.htmlThursday, August 19, 2010
REPORT ON THE INVESTIGATION OF THE SEVENTEENTH CASE OF BOVINE SPONGIFORM ENCEPHALOPATHY (BSE) IN CANADA
http://bseusa.blogspot.com/2010/08/report-on-investigation-of-seventeenth.htmlThursday, August 19, 2010
SCRAPIE CANADA UPDATE Current as of 2010-07-31 The following table lists sheep flocks and/or goat herds confirmed to be infected with scrapie in Canada in 2010.
Current as of: 2010-07-31
http://nor-98.blogspot.com/2010/08/scrapie-canada-update-current-as-of.html14th ICID International Scientific Exchange Brochure -
Final Abstract Number: ISE.114
Session: International Scientific Exchange
Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North America
update October 2009
T. Singeltary
Bacliff, TX, USA
Background:
An update on atypical BSE and other TSE in North America. Please remember, the typical U.K. c-BSE, the atypical l-BSE (BASE), and h-BSE have all been documented in North America, along with the typical scrapie's, and atypical Nor-98 Scrapie, and to date, 2 different strains of CWD, and also TME. All these TSE in different species have been rendered and fed to food producing animals for humans and animals in North America (TSE in cats and dogs ?), and that the trading of these TSEs via animals and products via the USA and Canada has been immense over the years, decades.
Methods:
12 years independent research of available data
Results:
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 2009. With all the science to date refuting it, to continue to validate this old myth, will only spread this TSE agent through a multitude of potential routes and sources i.e. consumption, medical i.e., surgical, blood, dental, endoscopy, optical, nutritional supplements, cosmetics etc.
Conclusion:
I would like to submit a review of past CJD surveillance in the USA, and the urgent need to make all human TSE in the USA a reportable disease, in every state, of every age group, and to make this mandatory immediately without further delay. The ramifications of not doing so will only allow this agent to spread further in the medical, dental, surgical arena's. Restricting the reporting of CJD and or any human TSE is NOT scientific. Iatrogenic CJD knows NO age group, TSE knows no boundaries. I propose as with Aguzzi, Asante, Collinge, Caughey, Deslys, Dormont, Gibbs, Gajdusek, Ironside, Manuelidis, Marsh, et al and many more, that the world of TSE Transmissible Spongiform Encephalopathy is far from an exact science, but there is enough proven science to date that this myth should be put to rest once and for all, and that we move forward with a new classification for human and animal TSE that would properly identify the infected species, the source species, and then the route.
http://ww2.isid.org/Downloads/14th_ICID_ISE_Abstracts.pdfWednesday, March 31, 2010
Atypical BSE in Cattle
http://bse-atypical.blogspot.com/2010/03/atypical-bse-in-cattle-position-post.htmllet'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.1000156http://www.plospathogens.org/article/fetchObjectAttachment.action?uri=info%3Adoi%2F10.1371%2Fjournal.ppat.1000156&representation=PDFSaturday, 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.htmlFRIENDLY FIRE FROM ALL OF THE ABOVE ;
Wednesday, August 18, 2010
Incidence of CJD Deaths Reported by CJD-SS in Canada as of July 31, 2010
http://creutzfeldt-jakob-disease.blogspot.com/2010/08/incidence-of-cjd-deaths-reported-by-cjd.htmlSunday, April 18, 2010
SCRAPIE AND ATYPICAL SCRAPIE TRANSMISSION STUDIES A REVIEW 2010
http://scrapie-usa.blogspot.com/2010/04/scrapie-and-atypical-scrapie.htmlTSS
Thursday, August 19, 2010
SCRAPIE CANADA UPDATE Current as of 2010-07-31 The following table lists sheep flocks and/or goat herds confirmed to be infected with scrapie in Canada in 2010.
Current as of: 2010-07-31
http://nor-98.blogspot.com/2010/08/scrapie-canada-update-current-as-of.htmlMonday, 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.htmlThursday, August 12, 2010
USA Blood products, collected from a donor who was at risk for vCJD, were distributed July-August 2010
http://creutzfeldt-jakob-disease.blogspot.com/2010/08/usa-blood-products-collected-from-donor.htmlTSS
