Monday, January 13, 2014

Prions in Variably Protease-Sensitive Prionopathy: An Update Pathogens 2013

Pathogens 2013, 2, 457-471; doi:10.3390/pathogens2030457

 

pathogens

 

ISSN 2076-0817

 


 

 

Review

 

 

Prions in Variably Protease-Sensitive Prionopathy: An Update

 

 

Wen-Quan Zou 1,2,3,4,5,6,*, Pierluigi Gambetti 1,3, Xiangzhu Xiao 1, Jue Yuan 1, Jan Langeveld 7 and Laura Pirisinu 8

 

1 Department of Pathology Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; E-Mails: pxg13@case.edu (P.G.); xiangzhu.xiao@case.edu (X.X.); jue.yuan@case.edu (J.Y.)

 

2 Department of Neurology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA

 

3 National Prion Disease Pathology Surveillance Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA

 

4 National Center for Regenerative Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA

 

5 The First Affiliated Hospital, Nanchang University, Nanchang 330006, Jiangxi Province, China

 

6 State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 100050, China

 

7 Central Veterinary Institute of Wageningen UR, Lelystad 8200 AB, the Netherlands; E-Mail: jan.langeveld@wur.nl (J.L.)

 

8 Department of Veterinary Public Health and Food Safety, Istituto Superiore di Sanità, Viale Regina Elena 299 00161, Rome, Italy; E-Mail: laura.pirisinu@guest.iss.it (L.P.)

 

* Author to whom correspondence should be addressed; E-Mail: wenquan.zou@case.edu; Tel./Fax: +1-216-368-8993/+1-216-368-2546.

 

Received: 12 June 2013; in revised form: 28 June 2013 / Accepted: 2 July 2013 /

 

Published: 5 July 2013

 

Abstract: Human prion diseases, including sporadic, familial, and acquired forms such as Creutzfeldt-Jakob disease (CJD), are caused by prions in which an abnormal prion protein (PrPSc) derived from its normal cellular isoform (PrPC) is the only known component. The recently-identified variably protease-sensitive prionopathy (VPSPr) is characterized not only by an atypical clinical phenotype and neuropathology but also by the deposition in the brain of a peculiar PrPSc. Like other forms of human prion disease, the pathogenesis of VPSPr also currently remains unclear. However, the findings of the peculiar features of prions from VPSPr and of the possible association of VPSPr with a known genetic prion disease linked with a valine to isoleucine mutation at residue 180 of PrP reported recently, may be of great importance in enhancing our understanding of not only this atypical human prion disease in particular, but also other prion diseases in general. In this review, we highlight the physicochemical and biological properties of prions from VPSPr and discuss the pathogenesis of VPSPr including the origin and formation of the peculiar prions.

 

Keywords: prions; prion protein; prion disease; Creutzfeldt-Jakob disease (CJD); variably protease-sensitive prionopathy (VPSPr); Gerstmann-Sträussler-Scheinker (GSS); mutation; proteinase K; antibody; glycosylation; glycoform-selective prion formation; transmissibility

 

SNIP...

 

Pathogens 2013, 2 466

 

8. Origin of Prions in VPSPr and fCJDV180I As mentioned above, prions from VPSPr and fCJDV18°I are of unique physicochemical and biological properties. Remarkably, they exhibit a high immunoreactivity with the 1E4 antibody but a poor reactivity with 3F4 [5,6]. We have demonstrated that the two antibodies have adjacent epitopes and especially the 3F4 epitope (PrP106-112) is next to the C-terminus of the 1E4 epitope (PrP97-105) [9,40]. Because of the unique localization of the two epitopes, it is most likely that all five-step like rPrPSc fragments from the two diseases contain the 3F4 epitope. So, the poor affinity of 3F4 for rPrPSc from VPSPr and fCJDV180I may indicate that there might be some local structures or binding molecules that block the 3F4 epitope. We have noticed that the affinity of 3F4 for rPrPSc from VPSPr was increased in the preparations after purification steps compared to unpurified total brain homogenates (Zou et al., unpublished data). Thus, purification procedures may somehow remove the binding molecules or alter the local structures, which might make the 3F4 epitope exposed. On the other hand, all these findings may also suggest that PrPSc from VPSPr and fCJDV180I have an origin different from PrPSc detected in other human prion diseases. Using the same 1E4 antibody, we previously identified a PK-resistant PrP species termed insoluble PrPC (iPrPC) in uninfected human brains and cultured cells [6,9,40,41,42]. The small amount of PK-resistant PrP in uninfected brains and cells exhibited the same peculiar immunoreactivity behavior: higher affinity for 1E4 but lower affinity for 3F4. Remarkably, the resemblances of three PK-resistant PrP core fragments migrating at ~20 kDa, 17 kDa and 7 kDa observed in VPSPr were detected with 1E4 in uninfected human brains [43]. The same immunoreactivity behavior of iPrPC in uninfected brains and rPrPSc in VPSPr and fCJDV180I suggests that they may share a common molecular metabolic pathway or distribution and that VPSPr and fCJDV180I may result from an increase in the amount of iPrPC [43].

 

SNIP...

 

9. Association between VPSPr and Other Prion Diseases

 

In addition to V180I and T183A mutations, three other naturally occurring PrP mutations including D178N, F198S, and E200K linked to familial prion disease have reportedly been associated with altered ratios of the three PrP glycoforms. But all the three familial prion diseases do not have rPrPSc that lacks diglycosylated form [39]. Moreover, the 1E4-preferentially detectable rPrPSc has not been identified yet. The deposition in the brain of multiple small PK-resistant PrPSc, especially the 7-kDa fragment is the molecular hallmark of GSS [44]. Therefore, it is reasonable for us to anticipate some potential association between GSS and VPSPr. Indeed, because of the long disease duration, multiple PK-resistant PrP fragments, and variable PK-resistance of PrPSc, VPSPr was once suspected to be the sporadic form of GSS associated with PrPA117V mutation (GSSA117) [5]. However, we also observed different ratios and immunoreactivity of PrPSc between VPSPr and GSSA117V in the same study. It is known that GSS is frequently associated with a predominantly cerebellar dysfunction and is mainly characterized by the deposition of multicentric plaques in the cerebellum [39]. In contrast, VPSPr lacks typical multicentric plaques while it exhibits dot-like staining or small plaque-like formations in the cerebellum [5]. Whether VPSPr is the sporadic form of fCJDV180I or GSSA117V needs to be further determined. It is conceivable that cells and animals expressing human PrPV180I or PrPA117V will provide valid models for addressing the outstanding questions.

 

 Pathogens 2013, 2 467

 

The fact that a small PK-resistant rPrPSc migrating at ~6–7 kDa that has been believed to be a molecular hallmark of various GSS is also detectable in both VPSPr and Nor98 [2,5,7,34,35,44] may imply a possible association among these diseases. To gain insights into their apparent similarity and difference and to investigate possible relationships among them, we further compared the small fragment from VPSPr, Nor98, various GSS linked to P102L, A117V, or F198S PrP mutation [8,45]. It was demonstrated that VPSPr and Nor98 share both similar and distinctive features. For instance, interestingly, they all have a core rPrPSc fragment encompassing PrP97-142 while the fragment can have varied N- and C-terminal cleavage sites (Table 1) [45].

 

 10. Conclusions

 

Prions found in sporadic VPSPr are clearly different from those of all other classic sporadic human prion diseases. Both VPSPr and fCJDV180I shares similar physicochemical properties of PrPSc and a glycoform-selective prion formation pathway. The finding of the effect of polymorphism at residue 129 on the levels of rPrPSc and sPrPSc further emphasizes the role of the polymorphism in the pathogenesis of human prion diseases. The two diseases specifically alter glycosylation at the first glycosylation site at residue 181 of PrP, which may involve a non-PrP protein that participates in regulating PrP glycosylation. Because of similar immunoreactivity and enzymatic fragmentation, PrPSc in VPSPr and fCJDV180I may have an origin similar to iPrPC. The possible correlation between human VPSPr and sheep Nor98 is interesting but remains to be further investigated. The low transmissibility of VPSPr and fCJDV180I may result from altered posttranslational modifications including not only glycosylation but also the glycophosphatidylinositol (GPI) anchor. Whether there are any changes in GPI anchor remains unknown. Our current protein sequencing study and glycan analysis of purified rPrPSc will provide insights into these issues. Future studies with the two diseases and with cell and animal models expressing PrPV180I mutation will help us understand the possible co-factors and molecular mechanisms underlying the formation of the unique prions identified in VPSPr and fCJDV180I.

 

 


 

 

Prions in Variably Protease-Sensitive Prionopathy- An ... - MDPI.com

 

 


 

 

 

_sporadic_ FFI,

 

 

_sporadic_ GSS,

 

 

and

 

 

_vpspr_

 

 

vpspr - None of the subjects had mutations in the PrP gene coding region.

 


 

 

sporadic FFI - Genetic tests identified no prion protein (PrP) gene mutation

 


 

 

Monday, January 14, 2013

 

snip...

 

Gambetti et al USA Prion Unit change another highly suspect USA mad cow victim to another fake name i.e. sporadic FFI at age 16 CJD Foundation goes along with this BSe

 

Only months later would Michael’s family learn the reason for his degradation and death. An autopsy showed that the teenager died of sporadic fatal insomnia, a subtype of Creutzfeldt-Jakob Disease.

 

In fact, Michael may be among the youngest ever to be affected by a neurodegenerative disease without an inherited or outside cause.

 

Gambetti, who played a key role in the discovery of fatal insomnia, theorizes that Michael’s illness was random, despite the odds. It may be that, by chance or some unknown factor, Michael’s brain perfectly bred its own pathogen.

 

snip...

 


 

 

sporadic GSS -

 

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.

 


 

 

Saturday July 6, 2013

 

Nor98 Prions Share Biochemical Features with Human Gerstmann-Sträussler-Scheinker Disease and Variably Protease-Sensitive Prionopathy

 


 


 

 

 

because there is _NO_ genetic link to that particular family, the theory of a familial disease is out the door, in my opinion. there has to be a source, route, and mode of transmission, if there is no genetic link to the family.

 

 

SPONTANEOUS HAS NEVER EVER BEEN PROVEN IN ANY CASE OF HUMAN TSE, ESPECIALLY IN 85%+ OF ALL HUMAN TSE PRION CASES, AND THE FOLLOWING STATEMENT HAS NO SCIENTIFIC PROOF;

 

 

*** ''Gambetti, who played a key role in the discovery of fatal insomnia, theorizes that Michael’s illness was random, despite the odds. It may be that, by chance or some unknown factor, Michael’s brain perfectly bred its own pathogen.''

 

 

WHAT POLITICAL TSE PRION SCIENCE HAS DONE, IS TAKEN THE WORDS OF THEORY AND HYPOTHESIS FROM SCIENTIST, AND THEN PUT IT IN PRINT, MADE THEM FACT, a terrible and unjust thing to do, for the scientific community, and society.

 

I would personally donate money to someone that WAS looking for a cause of the sporadic CJD, i.e. 85%+ of all human TSE prion disease.

 

now, that’s just my opinion, after watching the ‘FDA TRAVELING ROAD SHOW’, OR what I call the FDA TRAVELING THREE RING CIRCUS I.E. FDA, USDA, CDC.

 

 

(8:30 a.m.)

 

CHAIRMAN BROWN: My name is Dr. Paul Brown. Welcome to the FDA traveling road show. We are asked yet once more by the FDA to consider a question of theoretical risk in the absence of sufficient knowledge on which to base any firm conclusion.

 

The issue before us today is that of excluding categories of American blood donors who have either visited or resided for longer periods of time in Great Britain. The issue is sufficiently delicate, as you see that we have been moved outside the Beltway.

 

(Laughter.)



 

 


 


 


 

 

 

wonder who’s laughing now ???

 

 

no TSEAC MEETINGS IN HOW LONG ???

 

 

Wednesday, December 11, 2013

 

*** Detection of Infectivity in Blood of Persons with Variant and Sporadic Creutzfeldt-Jakob Disease ***

 


 

 

 

I ALSO STRONGLY DISAGREE WITH THE STATEMENT;

 

 

'OR OUTSIDE CAUSE'

 

 

IF THERE IS NO ;

 

 

'WITHOUT AN INHERITED CAUSE'

 

 

THEN THERE MUST BE AN OUTSIDE CAUSE, AND I PROPOSED, IN SOME CASES, IT BE IATROGENIC.

 

 

VPSPR TSE PRION IS TRANSMISSIBLE ;

 

 

please see ;

 

Conclusions. Preliminary results from transmission studies in bank voles strongly support the notion that VPSPr is a transmissible prion disease. Interestingly, VPSPr undergoes divergent evolution in the two genetic lines of voles, with sCJD-like features in BvM109 and GSS-like properties in BvI109.

 


 

 

GSS TSE PRION IS TRANSMISSIBLE ;

 

Acta Neuropathol. 1984;64(1):85-8.

 

Experimental transmission of human subacute spongiform encephalopathy to small rodents. IV. Positive transmission from a typical case of Gerstmann-Sträussler-Scheinker's disease.

 

Tateishi J, Sato Y, Nagara H, Boellaard JW.

 

Abstract

 

Spongiform encephalopathy was transmitted to mice from a patient belonging to the "Sch" family with Gerstmann-Sträussler-Scheinker's disease (GSS). Incubation periods in the first passage were much shorter than those in mice infected with Creutzfeldt-Jakob disease. Clinical and pathologic findings of mice infected with both diseases were almost identical. This is the first successful transmission from a typical GSS case without severe spongiform change which suggests the possible transmissible nature of this disorder.

 


 

 

FFI TSE PRION IS TRANSMISSIBLE ;

 

Nature 376, 434 - 435 (03 August 2002); doi:10.1038/376434a0

 

First experimental transmission of fatal familial insomnia

 

Jun Tateishi*, Paul Brown‡, Tetsuyuki Kitamoto*, Zahirul M. Hoque*, Raymond Roos§, Robert Wollman∥, Larisa Cervenàkovà ‡ & D. Carleton Gajdusek‡

 

* Department of Neuropathology, Neurological Institute, Kyushu University, Fukuoka 812, Japan ‡ Laboratory of CMS Studies, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Mayland 20892, USA Departments of Neurology § and Pathology∥, University of Chicago Medical Center, Chicago, Illinois 60637, USA

 

ORIGINALLY described by Lugaresi et al. in 1986 (ref. 1), fatal familial insomnia (FFI) is a rare inherited neurological disease characterized by the subacute progression of intractable insomnia and other autonomic abnormalities, cerebellar and pyramidal signs, myoclonus and dementia; neuropathologically, the major feature is severe neuronal loss with associated gliosis in the ventral and mediodorsal thalamic nuclei. The disease has been related to the group of spongiform encephalopathies by virtue of the presence of low levels of proteinase-resistant amyloid protein (PrPres) in the brain2á¤-4, and of a pathogenic single-allele mutation at codon 178 of the PRNP gene that encodes PrF68 (refs 2, 5). Here we report the successful transmission of the disease to experimental animals, placing FFI within the group of infectious cerebral amyloidoses.

 


 

 

Tuesday, August 03, 2010

 

Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein

 


 

 

Monday, August 9, 2010

 

Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein or just more PRIONBALONEY ?

 

snip...see full text ;

 


 

 

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. ...

 


 


 


 


 

 

Sunday, August 09, 2009

 

CJD...Straight talk with...James Ironside...and...Terry Singeltary... 2009

 


 

 

Tuesday, August 18, 2009

 

BSE-The Untold Story - joe gibbs and singeltary 1999 - 2009

 


 

 

PPS POLITICAL PRION SCIENCE $$$

 

Creutzfeldt-Jakob Disease Surveillance in Texas

 


 

 

Sunday, July 11, 2010

 

CJD or prion disease 2 CASES McLennan County Texas population 230,213 both cases in their 40s

 


 


 

 

I propose that the sporadic aspect of any familial disease is from a transmissible event, either iatrogenic, consumption, environmental, that's my theory, hypothesis, story, whatever you want to call it, and I'm sticking to it, until science proves to me, it's wrong. to date, science has not proven that any of the 85%+ of all human TSE prion disease is of a sporadic or spontaneous event, a happenstance of bad luck, just happens. that's just the political/industrial science, nature of the beast i.e. MONEY $$$ talking, in my opinion. ...

 

 

Friday, January 10, 2014

 

vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type prion disease, what it ???

 


 

 

 

what will different strains of CWD in cervids, look like in humans ???

 

 

Wednesday, January 01, 2014

 

 

Molecular Barriers to Zoonotic Transmission of Prions

 

 

*** chronic wasting disease, there was no absolute barrier to conversion of the human prion protein.

 

*** Furthermore, the form of human PrPres produced in this in vitro assay when seeded with CWD, resembles that found in the most common human prion disease, namely sCJD of the MM1 subtype.

 

 


 

 


 

 

 

Thursday, January 2, 2014

 

*** CWD TSE Prion in cervids to hTGmice, Heidenhain Variant Creutzfeldt-Jacob Disease MM1 genotype, and iatrogenic CJD ???

 


 

 

 

*** The discovery of previously unrecognized prion diseases in both humans and animals (i.e., Nor98 in small ruminants) demonstrates that the range of prion diseases might be wider than expected and raises crucial questions about the epidemiology and strain properties of these new forms. We are investigating this latter issue by molecular and biological comparison of VPSPr, GSS and Nor98.

 

Increased Atypical Scrapie Detections

 

Press reports indicate that increased surveillance is catching what otherwise would have been unreported findings of atypical scrapie in sheep. In 2009, five new cases have been reported in Quebec, Ontario, Alberta, and Saskatchewan. With the exception of Quebec, all cases have been diagnosed as being the atypical form found in older animals. Canada encourages producers to join its voluntary surveillance program in order to gain scrapie-free status. The World Animal Health will not classify Canada as scrapie-free until no new cases are reported for seven years. The Canadian Sheep Federation is calling on the government to fund a wider surveillance program in order to establish the level of prevalence prior to setting an eradication date. Besides long-term testing, industry is calling for a compensation program for farmers who report unusual deaths in their flocks.

 


 

 

Thursday, March 29, 2012

 

atypical Nor-98 Scrapie has spread from coast to coast in the USA 2012

 

NIAA Annual Conference April 11-14, 2011San Antonio, Texas

 


 

 

Monday, April 25, 2011

 

Experimental Oral Transmission of Atypical Scrapie to Sheep

 

Volume 17, Number 5-May 2011 However, work with transgenic mice has demonstrated the potential susceptibility of pigs, with the disturbing finding that the biochemical properties of the resulting PrPSc have changed on transmission (40).

 


 

 

Monday, December 14, 2009

 

Similarities between Forms of Sheep Scrapie and Creutzfeldt-Jakob Disease Are Encoded by Distinct Prion Types

 

(hmmm, this is getting interesting now...TSS)

 

Sporadic CJD type 1 and atypical/ Nor98 scrapie are characterized by fine (reticular) deposits,

 

see also ;

 

All of the Heidenhain variants were of the methionine/ methionine type 1 molecular subtype.

 


 

 

see full text ;

 

 

Monday, December 14, 2009

 

Similarities between Forms of Sheep Scrapie and Creutzfeldt-Jakob Disease Are Encoded by Distinct Prion Types

 


 

 

Friday, March 09, 2012

 

Experimental H-type and L-type bovine spongiform encephalopathy in cattle: observation of two clinical syndromes and diagnostic challenges

 

Research article

 


 

 

Thursday, June 23, 2011

 

Experimental H-type bovine spongiform encephalopathy characterized by plaques and glial- and stellate-type prion protein deposits

 


 

 

P03.141

 

Aspects of the Cerebellar Neuropathology in Nor98

 

Gavier-Widén, D1; Benestad, SL2; Ottander, L1; Westergren, E1 1National Veterinary Insitute, Sweden; 2National Veterinary Institute,

 

Norway Nor98 is a prion disease of old sheep and goats. This atypical form of scrapie was first described in Norway in 1998. Several features of Nor98 were shown to be different from classical scrapie including the distribution of disease associated prion protein (PrPd) accumulation in the brain. The cerebellum is generally the most affected brain area in Nor98. The study here presented aimed at adding information on the neuropathology in the cerebellum of Nor98 naturally affected sheep of various genotypes in Sweden and Norway. A panel of histochemical and immunohistochemical (IHC) stainings such as IHC for PrPd, synaptophysin, glial fibrillary acidic protein, amyloid, and cell markers for phagocytic cells were conducted. The type of histological lesions and tissue reactions were evaluated. The types of PrPd deposition were characterized. The cerebellar cortex was regularly affected, even though there was a variation in the severity of the lesions from case to case. Neuropil vacuolation was more marked in the molecular layer, but affected also the granular cell layer. There was a loss of granule cells. Punctate deposition of PrPd was characteristic. It was morphologically and in distribution identical with that of synaptophysin, suggesting that PrPd accumulates in the synaptic structures. PrPd was also observed in the granule cell layer and in the white matter. The pathology features of Nor98 in the cerebellum of the affected sheep showed similarities with those of sporadic Creutzfeldt-Jakob disease in humans.

 

***The pathology features of Nor98 in the cerebellum of the affected sheep showed similarities with those of sporadic Creutzfeldt-Jakob disease in humans.

 


 

 

PR-26

 

NOR98 SHOWS MOLECULAR FEATURES REMINISCENT OF GSS

 

R. Nonno1, E. Esposito1, G. Vaccari1, E. Bandino2, M. Conte1, B. Chiappini1, S. Marcon1, M. Di Bari1, S.L. Benestad3, U. Agrimi1 1 Istituto Superiore di Sanità, Department of Food Safety and Veterinary Public Health, Rome, Italy (romolo.nonno@iss.it); 2 Istituto Zooprofilattico della Sardegna, Sassari, Italy; 3 National Veterinary Institute, Department of Pathology, Oslo, Norway

 

Molecular variants of PrPSc are being increasingly investigated in sheep scrapie and are generally referred to as "atypical" scrapie, as opposed to "classical scrapie". Among the atypical group, Nor98 seems to be the best identified. We studied the molecular properties of Italian and Norwegian Nor98 samples by WB analysis of brain homogenates, either untreated, digested with different concentrations of proteinase K, or subjected to enzymatic deglycosylation. The identity of PrP fragments was inferred by means of antibodies spanning the full PrP sequence. We found that undigested brain homogenates contain a Nor98-specific PrP fragment migrating at 11 kDa (PrP11), truncated at both the C-terminus and the N-terminus, and not N-glycosylated. After mild PK digestion, Nor98 displayed full-length PrP (FL-PrP) and N-glycosylated C-terminal fragments (CTF), along with increased levels of PrP11. Proteinase K digestion curves (0,006-6,4 mg/ml) showed that FL-PrP and CTF are mainly digested above 0,01 mg/ml, while PrP11 is not entirely digested even at the highest concentrations, similarly to PrP27-30 associated with classical scrapie. Above 0,2 mg/ml PK, most Nor98 samples showed only PrP11 and a fragment of 17 kDa with the same properties of PrP11, that was tentatively identified as a dimer of PrP11. Detergent solubility studies showed that PrP11 is insoluble in 2% sodium laurylsorcosine and is mainly produced from detergentsoluble, full-length PrPSc. Furthermore, among Italian scrapie isolates, we found that a sample with molecular and pathological properties consistent with Nor98 showed plaque-like deposits of PrPSc in the thalamus when the brain was analysed by PrPSc immunohistochemistry. Taken together, our results show that the distinctive pathological feature of Nor98 is a PrP fragment spanning amino acids ~ 90-155. This fragment is produced by successive N-terminal and C-terminal cleavages from a full-length and largely detergent-soluble PrPSc, is produced in vivo and is extremely resistant to PK digestion.

 

*** Intriguingly, these conclusions suggest that some pathological features of Nor98 are reminiscent of Gerstmann-Sträussler-Scheinker disease.

 

119

 


 

 

A newly identified type of scrapie agent can naturally infect sheep with resistant PrP genotypes

 

Annick Le Dur*,?, Vincent Béringue*,?, Olivier Andréoletti?, Fabienne Reine*, Thanh Lan Laï*, Thierry Baron§, Bjørn Bratberg¶, Jean-Luc Vilotte?, Pierre Sarradin**, Sylvie L. Benestad¶, and Hubert Laude*,?? +Author Affiliations

 

*Virologie Immunologie Moléculaires and ?Génétique Biochimique et Cytogénétique, Institut National de la Recherche Agronomique, 78350 Jouy-en-Josas, France; ?Unité Mixte de Recherche, Institut National de la Recherche Agronomique-Ecole Nationale Vétérinaire de Toulouse, Interactions Hôte Agent Pathogène, 31066 Toulouse, France; §Agence Française de Sécurité Sanitaire des Aliments, Unité Agents Transmissibles Non Conventionnels, 69364 Lyon, France; **Pathologie Infectieuse et Immunologie, Institut National de la Recherche Agronomique, 37380 Nouzilly, France; and ¶Department of Pathology, National Veterinary Institute, 0033 Oslo, Norway

 

***Edited by Stanley B. Prusiner, University of California, San Francisco, CA (received for review March 21, 2005)

 

Abstract Scrapie in small ruminants belongs to transmissible spongiform encephalopathies (TSEs), or prion diseases, a family of fatal neurodegenerative disorders that affect humans and animals and can transmit within and between species by ingestion or inoculation. Conversion of the host-encoded prion protein (PrP), normal cellular PrP (PrPc), into a misfolded form, abnormal PrP (PrPSc), plays a key role in TSE transmission and pathogenesis. The intensified surveillance of scrapie in the European Union, together with the improvement of PrPSc detection techniques, has led to the discovery of a growing number of so-called atypical scrapie cases. These include clinical Nor98 cases first identified in Norwegian sheep on the basis of unusual pathological and PrPSc molecular features and "cases" that produced discordant responses in the rapid tests currently applied to the large-scale random screening of slaughtered or fallen animals. Worryingly, a substantial proportion of such cases involved sheep with PrP genotypes known until now to confer natural resistance to conventional scrapie. Here we report that both Nor98 and discordant cases, including three sheep homozygous for the resistant PrPARR allele (A136R154R171), efficiently transmitted the disease to transgenic mice expressing ovine PrP, and that they shared unique biological and biochemical features upon propagation in mice. *** These observations support the view that a truly infectious TSE agent, unrecognized until recently, infects sheep and goat flocks and may have important implications in terms of scrapie control and public health.

 


 

 

Monday, December 1, 2008

 

When Atypical Scrapie cross species barriers

 

Authors

 

Andreoletti O., Herva M. H., Cassard H., Espinosa J. C., Lacroux C., Simon S., Padilla D., Benestad S. L., Lantier F., Schelcher F., Grassi J., Torres, J. M., UMR INRA ENVT 1225, Ecole Nationale Veterinaire de Toulouse.France; ICISA-INlA, Madrid, Spain; CEA, IBiTec-5, DSV, CEA/Saclay, Gif sur Yvette cedex, France; National Veterinary Institute, Postboks 750 Sentrum, 0106 Oslo, Norway, INRA IASP, Centre INRA de Tours, 3738O Nouzilly, France.

 

Content

 

Atypical scrapie is a TSE occurring in small ruminants and harbouring peculiar clinical, epidemiological and biochemical properties. Currently this form of disease is identified in a large number of countries. In this study we report the transmission of an atypical scrapie isolate through different species barriers as modeled by transgenic mice (Tg) expressing different species PRP sequence.

 

The donor isolate was collected in 1995 in a French commercial sheep flock. inoculation into AHQ/AHQ sheep induced a disease which had all neuro-pathological and biochemical characteristics of atypical scrapie. Transmitted into Transgenic mice expressing either ovine or PrPc, the isolate retained all the described characteristics of atypical scrapie.

 

Surprisingly the TSE agent characteristics were dramatically different v/hen passaged into Tg bovine mice. The recovered TSE agent had biological and biochemical characteristics similar to those of atypical BSE L in the same mouse model. Moreover, whereas no other TSE agent than BSE were shown to transmit into Tg porcine mice, atypical scrapie was able to develop into this model, albeit with low attack rate on first passage.

 

Furthermore, after adaptation in the porcine mouse model this prion showed similar biological and biochemical characteristics than BSE adapted to this porcine mouse model. Altogether these data indicate.

 

(i) the unsuspected potential abilities of atypical scrapie to cross species barriers

 

(ii) the possible capacity of this agent to acquire new characteristics when crossing species barrier

 

These findings raise some interrogation on the concept of TSE strain and on the origin of the diversity of the TSE agents and could have consequences on field TSE control measures.

 


 

 

Friday, February 11, 2011

 

Atypical/Nor98 Scrapie Infectivity in Sheep Peripheral Tissues

 


 

 

RESEARCH

 

Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 5, May 2011

 

Experimental Oral Transmission of Atypical Scrapie to Sheep

 

Marion M. Simmons, S. Jo Moore,1 Timm Konold, Lisa Thurston, Linda A. Terry, Leigh Thorne, Richard Lockey, Chris Vickery, Stephen A.C. Hawkins, Melanie J. Chaplin, and John Spiropoulos

 

To investigate the possibility of oral transmission of atypical scrapie in sheep and determine the distribution of infectivity in the animals’ peripheral tissues, we challenged neonatal lambs orally with atypical scrapie; they were then killed at 12 or 24 months. Screening test results were negative for disease-specifi c prion protein in all but 2 recipients; they had positive results for examination of brain, but negative for peripheral tissues. Infectivity of brain, distal ileum, and spleen from all animals was assessed in mouse bioassays; positive results were obtained from tissues that had negative results on screening. These fi ndings demonstrate that atypical scrapie can be transmitted orally and indicate that it has the potential for natural transmission and iatrogenic spread through animal feed. Detection of infectivity in tissues negative by current surveillance methods indicates that diagnostic sensitivity is suboptimal for atypical scrapie, and potentially infectious material may be able to pass into the human food chain.

 

SNIP...

 

Although we do not have epidemiologic evidence that supports the effi cient spread of disease in the fi eld, these data imply that disease is potentially transmissible under fi eld situations and that spread through animal feed may be possible if the current feed restrictions were to be relaxed. Additionally, almost no data are available on the potential for atypical scrapie to transmit to other food animal species, certainly by the oral route. However, work with transgenic mice has demonstrated the potential susceptibility of pigs, with the disturbing fi nding that the biochemical properties of the resulting PrPSc have changed on transmission (40). The implications of this observation for subsequent transmission and host target range are currently unknown.

 

How reassuring is this absence of detectable PrPSc from a public health perspective? The bioassays performed in this study are not titrations, so the infectious load of the positive gut tissues cannot be quantifi ed, although infectivity has been shown unequivocally. No experimental data are currently available on the zoonotic potential of atypical scrapie, either through experimental challenge of humanized mice or any meaningful epidemiologic correlation with human forms of TSE. However, the detection of infectivity in the distal ileum of animals as young as 12 months, in which all the tissues tested were negative for PrPSc by the currently available screening and confi rmatory diagnostic tests, indicates that the diagnostic sensitivity of current surveillance methods is suboptimal for detecting atypical scrapie and that potentially infectious material may be able to pass into the human food chain undetected.

 

Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 17, No. 5, May 2011

 


 

 

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.

 


 

 

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.

 


 


 

 

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.

 


 

 

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.

 


 


 

 

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.

 


 

 

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.

 


 

 

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

 


 

 

PLEASE READ FULL TEXT ;

 


 

 

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.

 


 

 

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.

 


 


 

 

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

 


 

 

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)

 


 

 

why do we not want to do TSE transmission studies on chimpanzees $

 

 

5. A positive result from a chimpanzee challenged severly would likely create alarm in some circles even if the result could not be interpreted for man. I have a view that all these agents could be transmitted provided a large enough dose by appropriate routes was given and the animals kept long enough. Until the mechanisms of the species barrier are more clearly understood it might be best to retain that hypothesis.

 

snip...

 

R. BRADLEY

 


 

 

1: J Infect Dis 1980 Aug;142(2):205-8

 

Oral transmission of kuru, Creutzfeldt-Jakob disease, and scrapie to nonhuman primates.

 

Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC.

 

Kuru and Creutzfeldt-Jakob disease of humans and scrapie disease of sheep and goats were transmitted to squirrel monkeys (Saimiri sciureus) that were exposed to the infectious agents only by their nonforced consumption of known infectious tissues. The asymptomatic incubation period in the one monkey exposed to the virus of kuru was 36 months; that in the two monkeys exposed to the virus of Creutzfeldt-Jakob disease was 23 and 27 months, respectively; and that in the two monkeys exposed to the virus of scrapie was 25 and 32 months, respectively. Careful physical examination of the buccal cavities of all of the monkeys failed to reveal signs or oral lesions. One additional monkey similarly exposed to kuru has remained asymptomatic during the 39 months that it has been under observation.

 

snip...

 

The successful transmission of kuru, Creutzfeldt-Jakob disease, and scrapie by natural feeding to squirrel monkeys that we have reported provides further grounds for concern that scrapie-infected meat may occasionally give rise in humans to Creutzfeldt-Jakob disease.

 

PMID: 6997404

 


 

 

Recently the question has again been brought up as to whether scrapie is transmissible to man. This has followed reports that the disease has been transmitted to primates. One particularly lurid speculation (Gajdusek 1977) conjectures that the agents of scrapie, kuru, Creutzfeldt-Jakob disease and transmissible encephalopathy of mink are varieties of a single "virus". The U.S. Department of Agriculture concluded that it could "no longer justify or permit scrapie-blood line and scrapie-exposed sheep and goats to be processed for human or animal food at slaughter or rendering plants" (ARC 84/77)" The problem is emphasised by the finding that some strains of scrapie produce lesions identical to the once which characterise the human dementias"

 

Whether true or not. the hypothesis that these agents might be transmissible to man raises two considerations. First, the safety of laboratory personnel requires prompt attention. Second, action such as the "scorched meat" policy of USDA makes the solution of the acrapie problem urgent if the sheep industry is not to suffer grievously.

 

snip...

 

76/10.12/4.6

 


 

 

Nature. 1972 Mar 10;236(5341):73-4.

 

Transmission of scrapie to the cynomolgus monkey (Macaca fascicularis).

 

Gibbs CJ Jr, Gajdusek DC.

 

Nature 236, 73 - 74 (10 March 1972); doi:10.1038/236073a0

 

Transmission of Scrapie to the Cynomolgus Monkey (Macaca fascicularis)

 

C. J. GIBBS jun. & D. C. GAJDUSEK

 

National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, Maryland

 

SCRAPIE has been transmitted to the cynomolgus, or crab-eating, monkey (Macaca fascicularis) with an incubation period of more than 5 yr from the time of intracerebral inoculation of scrapie-infected mouse brain. The animal developed a chronic central nervous system degeneration, with ataxia, tremor and myoclonus with associated severe scrapie-like pathology of intensive astroglial hypertrophy and proliferation, neuronal vacuolation and status spongiosus of grey matter. The strain of scrapie virus used was the eighth passage in Swiss mice (NIH) of a Compton strain of scrapie obtained as ninth intracerebral passage of the agent in goat brain, from Dr R. L. Chandler (ARC, Compton, Berkshire).

 


 

 


 

 


 

 


 

 

 


Friday, August 16, 2013

*** Creutzfeldt-Jakob disease (CJD) biannual update August 2013 U.K. and Contaminated blood products induce a highly atypical prion disease devoid of PrPres in primates
http://creutzfeldt-jakob-disease.blogspot.com/2013/08/creutzfeldt-jakob-disease-cjd-biannual.html




WHAT about the sporadic CJD TSE proteins ?


WE now know that some cases of sporadic CJD are linked to atypical BSE and atypical Scrapie, so why are not MORE concerned about the sporadic CJD, and all it’s sub-types $$$

Creutzfeldt-Jakob Disease CJD cases rising North America updated report August 2013

*** Creutzfeldt-Jakob Disease CJD cases rising North America with Canada seeing an extreme increase of 48% between 2008 and 2010 ***
http://creutzfeldt-jakob-disease.blogspot.com/2013/08/creutzfeldt-jakob-disease-cjd-cases.html




Sunday, October 13, 2013

*** CJD TSE Prion Disease Cases in Texas by Year, 2003-2012
http://creutzfeldt-jakob-disease.blogspot.com/2013/10/cjd-tse-prion-disease-cases-in-texas-by.html

 
kind regards, terry

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