Atypical Scrapie Prions from Sheep and Lack of Disease in Transgenic Mice
Overexpressing Human Prion Protein
Jonathan D.F. Wadsworth, Susan Joiner, Jacqueline M. Linehan, Anne
Balkema-Buschmann, John Spiropoulos, Marion M. Simmons, Peter C. Griffiths,
Martin H. Groschup, James Hope, Sebastian Brandner, Emmanuel A. Asante, and John
Collinge
Public and animal health controls to limit human exposure to animal prions
are focused on bovine spongiform encephalopathy (BSE), but other prion strains
in ruminants may also have zoonotic potential. One example is atypical/Nor98
scrapie, which evaded statutory diagnostic methods worldwide until the early
2000s. To investigate whether sheep infected with scrapie prions could be
another source of infection, we inoculated transgenic mice that overexpressed
human prion protein with brain tissue from sheep with natural field cases of
classical and atypical scrapie, sheep with experimental BSE, and cattle with
BSE. We found that these mice were susceptible to BSE prions, but disease did
not develop after prolonged postinoculation periods when mice were inoculated
with classical or atypical scrapie prions. These data are consistent with the
conclusion that prion disease is less likely to develop in humans after exposure
to naturally occurring prions of sheep than after exposure to epizootic BSE
prions of ruminants.
snip...
Results
Scrapie Prions from Sheep and Lack of Disease in Transgenic Mice
We examined classical and atypical scrapie sheep brain homogenates from UK
field cases (AHVLA) that contain PK-resistant ovine PrPSc and efficiently
transmitted clinical prion disease to transgenic mice expressing ovine PrP
(21,22) (Table 1), together with a series of PK-resistant PrP-positive brain
homogenates from sheep in Germany with field cases of classical and atypical
scrapie (Figure 1). All natural brain isolates examined produced no clinical
prion disease or biochemical or histopathologic evidence for subclinical prion
infection in transgenic mice that overexpressed human PrP after postinoculation
intervals of >600 days (Table 2).
Consistent with the inability of IHC or high sensitivity immunoblotting to
detect pathologic PrP in the brains of inoculated mice, neuropathologic
examination of the brain showed no difference in spongiform change or gliosis
from that observed in the brains of age-matched control mice (data not shown).
From these findings, we conclude that both methionine and valine residue 129
variants of human PrP are refractory to pathologic conversion by these ovine
prion strains in transgenic mice.
Transmission of Cattle BSE Prions to Transgenic Mice Brain isolates from
sheep with classical and atypical scrapie (including those with demonstrated
prion infectivity in transgenic mice expressing ovine PrP) did not transmit
prion disease to transgenic mice that were overexpressing human PrP. This fact
contrasts markedly with the known susceptibility of these mice to transmission
of multiple cattle BSE isolates (2,4,24,25) as well as to transmission of a wide
range of human-acquired prion diseases (including kuru and vCJD) and sporadic
prion disease isolates (2,4,24–26).
Concomitant with the current study, and as part of a separate experiment,
we inoculated 129MM Tg35c mice intracerebrally with cattle BSE isolate I038.
This BSE isolate has previously been shown to be transmissible to the parent
129MM Tg35 transgenic line, producing an attack rate of 8/20 inoculated mice (4)
(Table 3). Affected 129MM Tg35 mice in these transmissions were culled (because
of intercurrent illness or clinical prion disease) within 600 days of
inoculation (Table 3) and demonstrated the presence of abnormal PrP in brain by
IHC and immunoblotting (4). In 129MM Tg35c mice, cattle BSE isolate I038
produced an attack rate of 5/12 in intracerebrally inoculated mice (Table 3).
Infection was characterized by the detection of abnormal PrP by IHC (Figure 2,
panels A, B), which included large amorphous PrP deposits (Figure 2, panels C,
E) and florid PrP plaques (Figure 2, panels D, F), and the detection of type 4
PrPSc in brain homogenate by immunoblotting (Figure 2, panel B inset).
Intercurrent illness before 600 days postinoculation was seen in only one 129MM
Tg35c mouse, with the remaining mice in the group (11/12) culled 611–853 days
postinoculation (Table 3).
Although most mice survived >600 days after inoculation, the attack rate
of cattle BSE isolate I038 in 129MM Tg35c mice remained the same as observed in
the parental 129MM Tg35 mouse line with ≈40% of inoculated mice becoming
infected (Table 3). In addition, we found that 129MM Tg35 and 129MM Tg35c mice
showed equivalent susceptibilities (100% attack rates) to vCJD or classical CJD
prions (Table 3).
snip...
Experimental Ovine BSE in Transgenic Mice Expressing Human PrP 129
Methionine
Recently, 2 studies have concluded that experimental sheep BSE prions may
propagate more efficiently than cattle BSE prions in transgenic mice that
express human PrP 129 methionine (17,34). One of these studies convincingly
established that sheep and goat BSE prions transmitted a molecular and
neuropathologic phenotype congruent with transmission of vCJD prions in the same
mice (17). These data strongly suggest that small ruminant BSE prions could act
as causal agents of vCJD (17). In this study, we also examined the transmission
properties of 2 experimental sheep BSE brain isolates derived from the primary
transmission and secondary passage of cattle BSE in sheep. These AHVLA isolates
were provided as brain homogenates that contained PK-resistant ovine PrP (Figure
3, panel A) and had known ability to transmit clinical prion disease to
wild-type RIII mice (Table 1).
In the transgenic mice expressing human PrP, clinical prion disease was not
produced by either of the 2 experimental sheep BSE isolates after
postinoculation intervals >600 days (Table 2). Examination of brain from
these inoculated mice by IHC and immunoblotting, after NaPTA precipitation of
brain homogenate, showed that only a single 129MM Tg35c recipient of the
secondary passage ovine BSE isolate had evidence of subclinical prion infection
(Table 2; Figure 3). This mouse was culled 661 days postinoculation when the
experiment was terminated. PrPSc was detectable in the brain of this transgenic
mouse without requirement for NaPTA precipitation for detection and appeared
similar (but not identical) to type 4 PrPSc seen in vCJD brain (Figure 3, panel
B). Florid PrP plaques were not observed, and abundant PrP deposits were
restricted to the corpus callosum (Figure 3, panel C), accompanied by occasional
punctate PrP deposits in the cortex and sparse diffuse PrP deposits in the
thalamus and hypothalamus (data not shown). Secondary passages of this isolate
in additional human PrP–expressing transgenic mice and wild-type FVB/N mice have
been initiated to comprehensively define prion strain type.
Why the efficiency of transmission of experimental sheep BSE prions to
129MM Tg35c mice is low compared with that reported in different lines of human
PrP 129 methionine–expressing mice (17,34) is unclear. One possible reason may
simply relate to the prion titers in the inocula. Plinston et al. reported that
2 different inocula prepared from the same experimental sheep BSE brain had
markedly different transmission efficiencies to genetargeted mice expressing
human PrP 129 methionine at endogenous levels (34). However, all AHVLA ovine
prion isolates used in this study were chosen because they produced short
survival periods and high attack rates in either ovine PrP transgenic mice or
wild type mice (Table 1). Therefore, other possibilities must also be
considered. In particular, studies involving different laboratories use
different lines of genetically modified mice. Variation in genetic background
and differences in PrP expression levels are known to influence host
susceptibility to prion infection (16).
Discussion
In this study, we have shown that disease does not develop in transgenic
mice overexpressing human PrP when mice are inoculated with ovine prions from
sheep with natural cases of classical scrapie and atypical scrapie from Great
Britain and Germany. These transgenic mice are susceptible to infection, and
clinical disease develops when mice are challenged with brain tissue from cattle
affected by classical BSE (2,4,24,25) or brain tissue from humans affected by
classical (sporadic and iatrogenic) CJD, kuru, or vCJD (2,4,24–26). Therefore,
this suggests that the transmission barrier associated with the interaction of
human PrP and the prion strain causing epizootic BSE in cattle is lower than
that associated with the prion strain causing atypical scrapie in sheep. Serial,
blind passage of brain homogenates from “negative” challenged mice from this
experiment into other lines of transgenic mice expressing either human PrP or
ovine PrP will now be required to determine whether this transmission barrier is
absolute.
Our findings complement those of other recent studies that have
investigated the zoonotic potential of ruminant prion strains using other lines
of human PrP–expressing mice. Gene-targeted human PrP–expressing mice have been
shown to be resistant to infection with classical and atypical scrapie prions
from sheep (34,35) and BSE prions from cattle (36) but are susceptible to
infection with BSE prions from sheep (34). Transgenic mice with 6-fold
overexpression of human PrP 129 methionine are susceptible to infection with
cattle BSE prions but show greater susceptibility to ovine and caprine BSE
prions (17).
Although we found evidence for transmission of experimental ovine BSE to
transgenic mice expressing human PrP 129 methionine, the relative attack rate
was lower than observed in the other lines of mice (17,34). The reasons
underlying this are not clear but may relate to differences in the prion
isolates themselves or differences in the various lines of mice. To definitively
investigate interlaboratory differences in the apparent behavior of ovine BSE
prions and reach a consensus, a panel of ovine prion inocula would need to
formally undergo endpoint titration across the different lines of humanized mice
and also in ovine PrP–expressing transgenic mice.
No strain variation has been found so far in the transmission, biochemical,
or histopathologic characteristics of atypical scrapie prions (22,37), and so
inferences from the present study are not confounded by sampling or strain
considerations. This is not so for cases of classical scrapie and, although our
findings on atypical scrapie prions indicate that the zoonotic potential of this
ovine prion strain is lower than for ruminant BSE prions, further transmission
studies using a wider variety of field cases of classical scrapie are required
to provide further reassurance of the low or negligible zoonotic potential of
all sheep prions. Examining extraneural tissues (in particular, the spleen) in
ovine prion-challenged mice will be critical because recent findings have shown
that cross-species prion transmission efficacy can exhibit a dramatic
tissue-dependence in the same host (38).
snip...see full text ;
Research Article
Small Ruminant Nor98 Prions Share Biochemical Features with Human
Gerstmann-Sträussler-Scheinker Disease and Variably Protease-Sensitive
Prionopathy
Laura Pirisinu, Romolo Nonno, Elena Esposito, Sylvie L. Benestad, Pierluigi
Gambetti, Umberto Agrimi, Wen-Quan Zou
Abstract
Prion diseases are classically characterized by the accumulation of
pathological prion protein (PrPSc) with the protease resistant C-terminal
fragment (PrPres) of 27–30 kDa. However, in both humans and animals, prion
diseases with atypical biochemical features, characterized by PK-resistant PrP
internal fragments (PrPres) cleaved at both the N and C termini, have been
described. In this study we performed a detailed comparison of the biochemical
features of PrPSc from atypical prion diseases including human
Gerstmann-Sträussler-Scheinker disease (GSS) and variably protease-sensitive
prionopathy (VPSPr) and in small ruminant Nor98 or atypical scrapie. The
kinetics of PrPres production and its cleavage sites after PK digestion were
analyzed, along with the PrPSc conformational stability, using a new method able
to characterize both protease-resistant and protease-sensitive PrPSc components.
All these PrPSc types shared common and distinctive biochemical features
compared to PrPSc from classical prion diseases such as sporadic
Creutzfeldt-Jakob disease and scrapie. Notwithstanding, distinct biochemical
signatures based on PrPres cleavage sites and PrPSc conformational stability
were identified in GSS A117V, GSS F198S, GSS P102L and VPSPr, which allowed
their specific identification. Importantly, the biochemical properties of PrPSc
from Nor98 and GSS P102L largely overlapped, but were distinct from the other
human prions investigated. Finally, our study paves the way towards more refined
comparative approaches to the characterization of prions at the animal–human
interface.
snip...
A prion disease with a similar low MW PrPres, Nor98 or atypical scrapie,
has been also described in small ruminants [35]. Firstly recognised in Norwegian
sheep in 1998 [36], a retrospective study in UK back-dated the presence of Nor98
cases to at least 1989, suggesting that these cases existed in small ruminant
populations for years without being detected [37]. Since 2002, Nor98 has been
identified in most of EU Member States [35], Canada [38], USA [39] and New
Zealand [40]. Unlike classical scrapie, Nor98 occurs with a sporadic
distribution [41], [42] and is diagnosed mainly in aged sheep and goats with
specific PrP polymorphisms [43], [44]. Although Nor98 is supposed to be a
spontaneous disorder [35], [42], [45], it is diagnosed at a relatively high
frequency in the EU, with a prevalence of ~4 over 10,000 examined [46]. Despite
the lack of epidemiological evidence for natural transmission of Nor98, its
transmissibility has been demonstrated in both ovinised transgenic mice [47] and
sheep [48], [49], and infectivity was also detected in peripheral tissues [49],
[50], indicating that potentially infectious material might enter the food
chain.
In this study we aimed at comparing the PrPSc properties of Nor98, GSS and
VPSPr cases, getting insight into their apparent similarity and investigating
possible relationships among them, particularly at the animal-human interface.
To this aim we set up refined biochemical techniques for inter-species
comparative epitope mapping of PrPres fragments and for determining the
conformational stability of both PK sensitive and PK resistant PrPSc species.
Our findings show that GSS, VPSPr and Nor98 share common and distinctive
biochemical features, supporting the notion that these atypical forms of PrPSc
are not uncommon and characterize a group of prion diseases with different
origins (genetic and spontaneous forms) occurring in different hosts. Within
this group, we found PrPSc biochemical signatures specific to VPSPr, GSS A117V
and GSS F198S, while the phenotypic profile of GSS P102L largely overlapped with
that of Nor98.
snip...
Overall, all Nor98 isolates contained highly PK resistant PrPres
aggregates, with the main PrPres being a non-glycosylated internal fragment,
cleaved at both the N and C termini, which represent the distinctive biochemical
feature of Nor98. This biochemical signature, unique among animal TSEs, is
reminiscent of PrPres observed in human prion disorders such as GSS and
VPSPr.
snip...
At present the only epidemiological link between animal and human TSEs has
been demonstrated for classical BSE and variant CJD [16], [78], showing for the
first time the zoonotic potential of TSEs. Since then, the implementation of
active surveillance in livestock has led to the identification of Nor98 and
other previously unrecognised animal prion strains, mainly with a sporadic
occurrence, whose origin and zoonotic potential are still poorly understood
[79]. It has been previously shown that peripheral tissues of sheep with Nor98
might harbour detectable levels of infectivity [49], [50], indicating that
infectious material might enter the food chain. On the other hand, the well
known genetic aetiology of GSS suggests that the similar PrPSc conformations
found in Nor98 and GSS P102L are unlikely to indicate a common infectious
source, but might derive from a similar molecular mechanisms involved in
PrPC-to-PrPSc conversion.
snip...
Citation: Pirisinu L, Nonno R, Esposito E, Benestad SL, Gambetti P, et al.
(2013) Small Ruminant Nor98 Prions Share Biochemical Features with Human
Gerstmann-Sträussler-Scheinker Disease and Variably Protease-Sensitive
Prionopathy. PLoS ONE 8(6): e66405. doi:10.1371/journal.pone.0066405
Editor: Corinne Ida Lasmezas, The Scripps Research Institute Scripps
Florida, United States of America
Received: January 24, 2013; Accepted: May 6, 2013; Published: June 24,
2013
Copyright: © 2013 Pirisinu et al. This is an open-access article
distributed under the terms of the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided
the original author and source are credited.
Funding: This work was supported by grants from the Italian Ministry of
Health (RF-2009-1474624); the European Union (Neuroprion Network of Excellence
CT-2004–506579); the National Institutes of Health (NIH) NS062787, NIH AG-08012,
AG-14359; Alliance BioSecure, as well as the Center for Disease Control and
Prevention Contract UR8/CCU515004. The funders had no role in study design, data
collection and analysis, decision to publish, or preparation of the
manuscript.
Competing interests: The authors have declared that no competing interests
exist.
*** 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.
VARIABLY PROTEASE-SENSITVE PRIONOPATHY IS TRANSMISSIBLE ...price of prion
poker goes up again $
OR-10: Variably protease-sensitive prionopathy is transmissible in bank
voles
Romolo Nonno,1 Michele Di Bari,1 Laura Pirisinu,1 Claudia D’Agostino,1
Stefano Marcon,1 Geraldina Riccardi,1 Gabriele Vaccari,1 Piero Parchi,2 Wenquan
Zou,3 Pierluigi Gambetti,3 Umberto Agrimi1 1Istituto Superiore di Sanità; Rome,
Italy; 2Dipartimento di Scienze Neurologiche, Università di Bologna; Bologna,
Italy; 3Case Western Reserve University; Cleveland, OH USA
Background. Variably protease-sensitive prionopathy (VPSPr) is a recently
described “sporadic”neurodegenerative disease involving prion protein
aggregation, which has clinical similarities with non-Alzheimer dementias, such
as fronto-temporal dementia. Currently, 30 cases of VPSPr have been reported in
Europe and USA, of which 19 cases were homozygous for valine at codon 129 of the
prion protein (VV), 8 were MV and 3 were MM. A distinctive feature of VPSPr is
the electrophoretic pattern of PrPSc after digestion with proteinase K (PK).
After PK-treatment, PrP from VPSPr forms a ladder-like electrophoretic pattern
similar to that described in GSS cases. The clinical and pathological features
of VPSPr raised the question of the correct classification of VPSPr among prion
diseases or other forms of neurodegenerative disorders. Here we report
preliminary data on the transmissibility and pathological features of VPSPr
cases in bank voles.
Materials and Methods. Seven VPSPr cases were inoculated in two genetic
lines of bank voles, carrying either methionine or isoleucine at codon 109 of
the prion protein (named BvM109 and BvI109, respectively). Among the VPSPr cases
selected, 2 were VV at PrP codon 129, 3 were MV and 2 were MM. Clinical
diagnosis in voles was confirmed by brain pathological assessment and western
blot for PK-resistant PrPSc (PrPres) with mAbs SAF32, SAF84, 12B2 and 9A2.
Results. To date, 2 VPSPr cases (1 MV and 1 MM) gave positive transmission
in BvM109. Overall, 3 voles were positive with survival time between 290 and 588
d post inoculation (d.p.i.). All positive voles accumulated PrPres in the form
of the typical PrP27–30, which was indistinguishable to that previously observed
in BvM109 inoculated with sCJDMM1 cases.
In BvI109, 3 VPSPr cases (2 VV and 1 MM) showed positive transmission until
now. Overall, 5 voles were positive with survival time between 281 and 596
d.p.i.. In contrast to what observed in BvM109, all BvI109 showed a GSS-like
PrPSc electrophoretic pattern, characterized by low molecular weight PrPres.
These PrPres fragments were positive with mAb 9A2 and 12B2, while being negative
with SAF32 and SAF84, suggesting that they are cleaved at both the C-terminus
and the N-terminus. Second passages are in progress from these first successful
transmissions.
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.
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.
Wednesday, March 28, 2012
VARIABLY PROTEASE-SENSITVE PRIONOPATHY IS TRANSMISSIBLE, price of prion
poker goes up again $
CANADA SEE STEADY INCREASE OF THE SPORADIC CJD’S AND THE VPSPR’S (sporadic
CJD’s). ...tss
PLEASE NOTE, type determination pending Creutzfeldt Jakob Disease (tdpCJD)
in Canada is also on a steady increase.
please see ;
> 3. Final classification of 50 cases from 2009, 2010, 2011 and 2012 is
pending.
CJD Deaths Reported by CJDSS1, 1994-20122
As of May 31, 2012
Deaths of Definite and Probable CJD
Year Sporadic Iatrogenic Familial GSS FFI vCJD Total
1994 2 0 0 1 0 0 3
1995 3 0 0 0 0 0 3
1996 13 0 0 0 0 0 13
1997 16 0 1 1 0 0 18
1998 22 1 0 1 0 0 24
1999 26 2 2 1 0 0 31
2000 32 0 0 3 0 0 35
2001 27 0 2 1 0 0 30
2002 31 0 2 2 0 1 36
2003 27 1 1 0 0 0 29
2004 42 0 1 0 0 0 43
2005 42 0 0 2 0 0 44
2006 39 0 1 3 1 0 44
2007 35 0 0 4 0 0 39
2008 48 0 1 0 0 0 49
2009 48 0 3 2 0 0 53
2010 34 0 3 0 0 0 37
2011 37 0 2 1 0 1 41
2012 1 0 0 0 0 0 1
Total 525 4 19 22 1 2 573
1. CJDSS began in 1998
2. Data before 1998 are retrospective and partial, data from 1998 to 2008
are complete, and data for 2009 - 2012 are provisional
3. Final classification of 50 cases from 2009, 2010, 2011 and 2012 is
pending.
CJD Deaths Reported by CJDSS1, 1994-20122
As of May 31, 2012
SEE DECEMBER 2012 CANADA
USA SEE STEADY INCREASE OF THE SPORADIC CJD’S AND THE VPSPR’S (sporadic
CJD’s). ...tss
National Prion Disease Pathology Surveillance Center
Cases Examined1
(May 18, 2012)
Year Total Referrals2 Prion Disease Sporadic Familial Iatrogenic vCJD
1996 & earlier 50 32 28 4 0 0
1997 114 68 59 9 0 0
1998 88 52 44 7 1 0
1999 123 74 65 8 1 0
2000 145 103 89 14 0 0
2001 210 120 110 10 0 0
2002 248 149 125 22 2 0
2003 266 168 137 31 0 0
2004 326 187 164 22 0 13
2005 344 194 157 36 1 0
2006 382 196 166 28 0 24
2007 377 213 185 28 0 0
2008 396 232 206 26 0 0
2009 423 256 212 43 1 0
2010 413 257 216 41 0 0
2011 410 257 213 43 0 0
2012 153 82 51 15 0 0
TOTAL 44685 26406 2227 387 6 3
1 Listed based on the year of death or, if not available, on year of
referral;
2 Cases with suspected prion disease for which brain tissue and/or blood
(in familial cases) were submitted;
3 Disease acquired in the United Kingdom;
4 Disease was acquired in the United Kingdom in one case and in Saudi
Arabia in the other case;
5 Includes 14 cases in which the diagnosis is pending, and 18 inconclusive
cases;
6 Includes 17 (16 from 2012) cases with type determination pending in which
the diagnosis of vCJD has been excluded. The Sporadic cases include 16 cases of
sporadic Fatal Insomnia (sFI) and 42 cases of Variably Protease-Sensitive
Prionopathy (VPSPr) and 2118 cases of sporadic Creutzfeldt-Jakob disease (sCJD).
Rev 5/18/2012
> 6 Includes
> 17 (16 from 2012) cases with type determination pending in which the
diagnosis of vCJD has been excluded.
> The Sporadic cases include 16 cases of sporadic Fatal Insomnia (sFI)
and 42 cases of Variably Protease-Sensitive Prionopathy (VPSPr) and 2118 cases
of sporadic Creutzfeldt-Jakob disease (sCJD).
WELL, it seems the USA mad cow strains in humans classified as type
determination pending tdpCJD, VPSPr, sFFI, and sCJD) have steadily increased
over the years, and the same old song and dance continues with sporadic CJD
cases $$$
Sunday, August 11, 2013
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 ***
Sunday, October 13, 2013
CJD TSE Prion Disease Cases in Texas by Year, 2003-2012
Wednesday, October 09, 2013
WHY THE UKBSEnvCJD ONLY THEORY IS SO POPULAR IN IT'S FALLACY, £41,078,281
in compensation REVISED
Thursday, October 10, 2013
CJD REPORT 1994 increased risk for consumption of veal and venison and lamb
Monday, October 14, 2013
***Researchers estimate one in 2,000 people in the UK carry variant CJD
proteins
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
*** 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
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6997404&dopt=Abstract
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).
Suspect symptoms
What if you can catch old-fashioned CJD by eating meat from a sheep
infected with scrapie?
28 Mar 01
Like lambs to the slaughter 31 March 2001 by Debora MacKenzie Magazine
issue 2284. Subscribe and get 4 free issues. FOUR years ago, Terry Singeltary
watched his mother die horribly from a degenerative brain disease. Doctors told
him it was Alzheimer's, but Singeltary was suspicious. The diagnosis didn't fit
her violent symptoms, and he demanded an autopsy. It showed she had died of
sporadic Creutzfeldt-Jakob disease.
Most doctors believe that sCJD is caused by a prion protein deforming by
chance into a killer. But Singeltary thinks otherwise. He is one of a number of
campaigners who say that some sCJD, like the variant CJD related to BSE, is
caused by eating meat from infected animals. Their suspicions have focused on
sheep carrying scrapie, a BSE-like disease that is widespread in flocks across
Europe and North America.
Now scientists in France have stumbled across new evidence that adds weight
to the campaigners' fears. To their complete surprise, the researchers found
that one strain of scrapie causes the same brain damage in mice as sCJD.
"This means we cannot rule out that at least some sCJD may be caused by
some strains of scrapie," says team member Jean-Philippe Deslys of the French
Atomic Energy Commission's medical research laboratory in Fontenay-aux-Roses,
south-west of Paris. Hans Kretschmar of the University of Göttingen, who
coordinates CJD surveillance in Germany, is so concerned by the findings that he
now wants to trawl back through past sCJD cases to see if any might have been
caused by eating infected mutton or lamb.
Scrapie has been around for centuries and until now there has been no
evidence that it poses a risk to human health. But if the French finding means
that scrapie can cause sCJD in people, countries around the world may have
overlooked a CJD crisis to rival that caused by BSE.
Deslys and colleagues were originally studying vCJD, not sCJD. They
injected the brains of macaque monkeys with brain from BSE cattle, and from
French and British vCJD patients. The brain damage and clinical symptoms in the
monkeys were the same for all three. Mice injected with the original sets of
brain tissue or with infected monkey brain also developed the same
symptoms.
As a control experiment, the team also injected mice with brain tissue from
people and animals with other prion diseases: a French case of sCJD; a French
patient who caught sCJD from human-derived growth hormone; sheep with a French
strain of scrapie; and mice carrying a prion derived from an American scrapie
strain. As expected, they all affected the brain in a different way from BSE and
vCJD. But while the American strain of scrapie caused different damage from
sCJD, the French strain produced exactly the same pathology.
"The main evidence that scrapie does not affect humans has been
epidemiology," says Moira Bruce of the neuropathogenesis unit of the Institute
for Animal Health in Edinburgh, who was a member of the same team as Deslys.
"You see about the same incidence of the disease everywhere, whether or not
there are many sheep, and in countries such as New Zealand with no scrapie." In
the only previous comparisons of sCJD and scrapie in mice, Bruce found they were
dissimilar.
But there are more than 20 strains of scrapie, and six of sCJD. "You would
not necessarily see a relationship between the two with epidemiology if only
some strains affect only some people," says Deslys. Bruce is cautious about the
mouse results, but agrees they require further investigation. Other trials of
scrapie and sCJD in mice, she says, are in progress.
People can have three different genetic variations of the human prion
protein, and each type of protein can fold up two different ways. Kretschmar has
found that these six combinations correspond to six clinical types of sCJD: each
type of normal prion produces a particular pathology when it spontaneously
deforms to produce sCJD.
But if these proteins deform because of infection with a disease-causing
prion, the relationship between pathology and prion type should be different, as
it is in vCJD. "If we look at brain samples from sporadic CJD cases and find
some that do not fit the pattern," says Kretschmar, "that could mean they were
caused by infection."
There are 250 deaths per year from sCJD in the US, and a similar incidence
elsewhere. Singeltary and other US activists think that some of these people
died after eating contaminated meat or "nutritional" pills containing dried
animal brain. Governments will have a hard time facing activists like Singeltary
if it turns out that some sCJD isn't as spontaneous as doctors have
insisted.
Deslys's work on macaques also provides further proof that the human
disease vCJD is caused by BSE. And the experiments showed that vCJD is much more
virulent to primates than BSE, even when injected into the bloodstream rather
than the brain. This, says Deslys, means that there is an even bigger risk than
we thought that vCJD can be passed from one patient to another through
contaminated blood transfusions and surgical instruments.
Sunday, December 12, 2010
EFSA reviews BSE/TSE infectivity in small ruminant tissues News Story 2
December 2010
Wednesday, January 18, 2012
Selection of Distinct Strain Phenotypes in Mice Infected by Ovine Natural
Scrapie Isolates Similar to CH1641 Experimental Scrapie
Journal of Neuropathology & Experimental Neurology: February 2012 -
Volume 71 - Issue 2 - p 140–147
Thursday, July 14, 2011
Histopathological Studies of "CH1641-Like" Scrapie Sources Versus Classical
Scrapie and BSE Transmitted to Ovine Transgenic Mice (TgOvPrP4)
Wednesday, January 18, 2012
BSE IN GOATS CAN BE MISTAKEN FOR SCRAPIE
February 1, 2012
Thursday, December 23, 2010
Molecular Typing of Protease-Resistant Prion Protein in Transmissible
Spongiform Encephalopathies of Small Ruminants, France, 2002-2009
Volume 17, Number 1 January 2011
Thursday, November 18, 2010
Increased susceptibility of human-PrP transgenic mice to bovine spongiform
encephalopathy following passage in sheep
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
Thursday, July 21, 2011
A Second Case of Gerstmann-Sträussler-Scheinker Disease Linked to the G131V
Mutation in the Prion Protein Gene in a Dutch Patient Journal of Neuropathology
& Experimental Neurology:
August 2011 - Volume 70 - Issue 8 - pp 698-702
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
Thursday, February 14, 2013
*** The Many Faces of Mad Cow Disease Bovine Spongiform Encephalopathy BSE
and TSE prion disease
Tuesday, March 5, 2013
Use of Materials Derived From Cattle in Human Food and Cosmetics; Reopening
of the Comment Period FDA-2004-N-0188-0051 (TSS SUBMISSION)
FDA believes current regulation protects the public from BSE but reopens
comment period due to new studies
Tuesday, March 05, 2013
A closer look at prion strains Characterization and important implications
Prion 7:2, 99–108; March/April 2013; © 2013 Landes Bioscience
Thursday, January 26, 2012
Facilitated Cross-Species Transmission of Prions in Extraneural Tissue
Science 27 January 2012: Vol. 335 no. 6067 pp. 472-475 DOI:
10.1126/science.1215659
Saturday, February 11, 2012
Prion cross-species transmission efficacy is tissue dependent
Thursday, January 26, 2012
The Risk of Prion Zoonoses
Science 27 January 2012: Vol. 335 no. 6067 pp. 411-413 DOI:
10.1126/science.1218167
Monday, April 25, 2011
Experimental Oral Transmission of Atypical Scrapie to Sheep
Volume 17, Number 5-May 2011
Sunday, April 18, 2010
SCRAPIE AND ATYPICAL SCRAPIE TRANSMISSION STUDIES A REVIEW 2010
Thursday, November 18, 2010
Increased susceptibility of human-PrP transgenic mice to bovine spongiform
encephalopathy following passage in sheep
Wednesday, January 19, 2011
EFSA and ECDC review scientific evidence on possible links between TSEs in
animals and humans Webnachricht 19 Januar 2011
Monday, June 27, 2011
Comparison of Sheep Nor98 with Human Variably Protease-Sensitive
Prionopathy and Gerstmann-Sträussler-Scheinker Disease
Thursday, November 18, 2010
Increased susceptibility of human-PrP transgenic mice to bovine spongiform
encephalopathy following passage in sheep
Tuesday, September 24, 2013
NORDION (US), INC., AND BIOAXONE BIOSCIENCES, INC., Settles $90M Mad Cow
TSE prion Contamination Suit Cethrin(R)
Case 0:12-cv-60739-RNS Document 1 Entered on FLSD Docket 04/26/2012 Page 1
of 15
with great sadness and disgust, I must inform you that our federal
government has failed us again, and chose the industry over sound science, with
regards to TSE prion disease, aka mad cow type disease...tss
Saturday, November 2, 2013
APHIS Finalizes Bovine Import Regulations in Line with International Animal
Health Standards while enhancing the spread of BSE TSE prion mad cow type
disease around the Globe
Monday, November 4, 2013
R-CALF Bullard new BSE rule represents the abrogation of USDA’s
responsibility to protect U.S. consumers and the U.S. cattle herd from the
introduction of foreign animal disease
TSS
