Article in Press
Proteinopathies, a core concept for understanding and ultimately treating
degenerative disorders?
Thomas A. Bayer Affiliations Tel.: +49 551 39 22912.
Received 18 October 2012; received in revised form 12 March 2013; accepted
24 March 2013. published online 03 May 2013. Corrected Proof
Abstract
The current review covers proteinopathies an umbrella term for
neurodegenerative disorders that are characterized by the accumulation of
specific proteins within neurons or in the brain parenchyma. Most prevalent
examples for typical proteinopathies are Alzheimer's disease and Parkinson's
disease. In healthy brain, these proteins are unstructured as a monomer, serving
most likely as the physiological form. In a disease condition, the unstructured
proteins experience a conformational change leading to small oligomers that
eventually will aggregate into higher order structures. Prion disease is an
exception within the family of proteinopathies as the aggregated prion protein
is highly infectious and can self-aggregate and propagate. Recent reports might
implicate a prion-like spread of misfolded proteins in Alzheimer's and
Parkinson's disease; however there are evident differences in comparison to
prion diseases. As proteinopathies are caused by the aggregation of
disease-typical proteins with an ordered structure, active and passive
immunization protocols have been used to expose model systems to therapeutic
antibodies that bind to the aggregates thereby inhibiting the prolongation into
higher ordered fibrils or dissolving the existing fibrillar structure. While
most of the immunization treatments have been only carried out in preclinical
model systems overexpressing the disease-relevant aggregating protein, other
approaches are already in clinical testing. Taking the core concept of
proteinopathies with conformationally altered protein aggregates into account,
immunization appears to be a very promising therapeutic option for
neurodegenerative disorders.
Keywords: Amyloid, Proteinopathy, Immunization, Clinical trial
Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem
proteinopathy and ALS
Hong Joo Kim, Nam Chul Kim, Yong-Dong Wang, Emily A. Scarborough, Jennifer
Moore, Zamia Diaz, Kyle S. MacLea, Brian Freibaum, Songqing Li, Amandine
Molliex, Anderson P. Kanagaraj, Robert Carter, Kevin B. Boylan, Aleksandra M.
Wojtas, Rosa Rademakers, Jack L. Pinkus, Steven A. Greenberg, John Q.
Trojanowski, Bryan J. Traynor, Bradley N. Smith, Simon Topp, Athina-Soragia
Gkazi, Jack Miller, Christopher E. Shaw, Michael Kottlors et al. Affiliations
Contributions Corresponding authors Nature 495,467–473(28 March
2013)doi:10.1038/nature11922Received 05 January 2012 Accepted 17 January 2013
Published online 03 March 2013
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Abstract
Abstract• Author information• Supplementary information Algorithms designed
to identify canonical yeast prions predict that around 250 human proteins,
including several RNA-binding proteins associated with neurodegenerative
disease, harbour a distinctive prion-like domain (PrLD) enriched in uncharged
polar amino acids and glycine. PrLDs in RNA-binding proteins are essential for
the assembly of ribonucleoprotein granules. However, the interplay between human
PrLD function and disease is not understood. Here we define pathogenic mutations
in PrLDs of heterogeneous nuclear ribonucleoproteins (hnRNPs) A2B1 and A1 in
families with inherited degeneration affecting muscle, brain, motor neuron and
bone, and in one case of familial amyotrophic lateral sclerosis. Wild-type
hnRNPA2 (the most abundant isoform of hnRNPA2B1) and hnRNPA1 show an intrinsic
tendency to assemble into self-seeding fibrils, which is exacerbated by the
disease mutations. Indeed, the pathogenic mutations strengthen a ‘steric zipper’
motif in the PrLD, which accelerates the formation of self-seeding fibrils that
cross-seed polymerization of wild-type hnRNP. Notably, the disease mutations
promote excess incorporation of hnRNPA2 and hnRNPA1 into stress granules and
drive the formation of cytoplasmic inclusions in animal models that recapitulate
the human pathology. Thus, dysregulated polymerization caused by a potent mutant
steric zipper motif in a PrLD can initiate degenerative disease. Related
proteins with PrLDs should therefore be considered candidates for initiating and
perhaps propagating proteinopathies of muscle, brain, motor neuron and bone.
Subject terms: Mechanisms of disease
Advances in Anatomic Pathology: September/October 1995 - Volume 2 - Issue 5
- ppg 314-319
Review Article: PDF Only
Prion Proteinopathies: Fatal Conversion
Goodman, Clay
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 $$$
VARIABLY PROTEASE-SENSITVE PRIONOPATHY IS TRANSMISSIBLE ...price of prion
poker goes up again $
OR-10 15:25 - 15:40 VARIABLY PROTEASE-SENSITIVE PRIONOPATHY IS
TRANSMISSIBLE IN BANK VOLES Nonno
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.
SOURCE PRION2012
I believe it was Gambetti et al that coined this term sporadic FFI, from
some conspicuous sub-type of sporadic CJD possibly? seems they could not tie it
to a true FFI by diagnostic standards to date, so it was then termed a sFFI,
confusing matters even worse. ...
A subtype of sporadic prion disease mimicking fatal familial insomnia
THIS seems to raise more questions than answers, confusing the TSEs even
worse.
WHAT is sporadic CJD, and how many sub-types and atypical strains,
phenotypes etc. will there be, arising from nothing. a spontaneous happening of
sorts???
i think not. ...tss
Wednesday, September 21, 2011
PrioNet Canada researchers in Vancouver confirm prion-like properties in
Amyotrophic Lateral Sclerosis (ALS)
PP1:
Does A “Prion-Like” Mechanism Contribute to the Spreading of Neuropathology
in Parkinson’s Disease?
Patrik Brundin Neuronal Survival Unit; Wallenberg Neuroscience Center; Dept
of Experimental Medical Science; Lund University; Lund, Sweden
Key words: Parkinson’s disease, prion mechanism, alpha-synuclein
Neuropathological aggregates of alpha-synuclein in neuronal cytoplasm and
neurites are typical features of Parkinson’s disease (PD). These Lewy neurites
and Lewy bodies are prominent in substantia nigra, where dopaminergic neurons
degenerate. With advancing disease they are also found in several other
widespread brain areas, and it has been suggested that they appear in anterior
olfactory structures and the dorsal motor nucleus of the vagal nerve even before
the substantia nigra is affected. Recent studies demonstrated that Lewy bodies
and neurites appear in grafted embryonic neurons.1-3 They stain for Thioflavin
S, are immunoreactive for alpha-synuclein phosphorylated at serine residue 129
and exhibit a fibrillar structure in the electron microscope.4 From 2 to 5%
(frequency increases over time) of the grafted dopaminergic neurons display Lewy
bodies, starting around one decade after surgery. Despite these changes, some of
the PD grafted patients still exhibit signs of functional recovery beyond a
decade after surgery. We, and others, are currently exploring possible
mechanisms underlying the transfer of alpha-synuclein between cells and their
relevance to how neuropathology normally spreads in the PD brain.5,6 We have
observed that alpha-synuclein indeed can transfer between cells in culture. The
process is clearly time-dependent and once inside the new cell the imported
alpha-synuclein can seed aggregation of endogenous alpha-synuclein. Furthermore,
we have observed transfer of host-derived alpha-synuclein into embryonic
dopamine neurons grafted into the striatum of transgenic mice expressing human
alpha-synuclein. We propose that a “prion-like” disease mechanism might
contribute to the pathogenesis of PD and other chronic neurodegenerative
disorders.6
References
1. Li, et al. Nat Med 2008; 14:501-3. 2. Kordower, et al. Nat Med 2008;
14:504-6. 3. Kordower, et al. Mov Disord 2008; 23:2303-6. 4. Li, et al. Mov
Disord 2010; [Epub ahead of print]. 5. Brundin, et al. Nat Rev Neurosci 2008;
9:741-5. 6. Brundin, et al. Nat Rev Mol Cell Biol 2010; 11:301-7. PP: Plenary
Lectures Previously published online:
www.landesbioscience.com/journals/prion/article/12765
DOI: 10.4161/pri.4.3.12765
===========================
WP8-4: Prion-like Induction of Alzheimer-type Proteopathy in Transgenic
Mice
Lary C. Walker
Yerkes Center; Emory University; Atlanta, GA USA
Key words: abeta, Alzheimer, amyloid, prion, seeding, strains, transgenic,
transmission
Alzheimer’s disease and prion disease both involve the accumulation of
disease-specific proteins in the brain, suggesting pathogenic commonalities. In
Alzheimer’s disease, the aggregation of the protein fragment Aßis a seminal
event. Similar to the templated corruption of prion protein, cerebral
Aßdeposition can be induced in ß-amyloid precursor protein (APP)-transgenic mice
and rats by the intracerebral injection of Aß-rich brain extracts from patients
with Alzheimer’s disease or APP-transgenic mice. Our studies indicate that the
characteristics of the seeded deposits depend on the source of the seeding
extract, the type of host, and the seeded brain region. We are using the
amyloid-binding agent Pittsburgh Compound B (PIB) as a marker of a potential
AD-specific form of multimeric Aß, and are attempting to induce alternative
conformations in the transgenic mouse Aß-seeding model. In addition, we are
investigating non-intracerebral routes of administration and the ability of
heterologous agents to induce Aßdeposition. Analysis of Aß-seeding in vivo could
yield fresh insights into the origins of idiopathic Alzheimer’s disease.
Acknowledgements
Key collaborators on these studies are Mathias Jucker (U. Tübingen),
Rebecca Rosen (Emory U.) and Harry LeVine III (U. Kentucky). Supported by NIH
RR-00165 and the CART Foundation.
===========================
PPo9-1: Prion-like Propagation of SOD1 Misfolding in Amyotrophic Lateral
Sclerosis
Neil R. Cashman
University of British Columbia; Vancouver, British Columbia Canada
Key words: protein misfolding, mechanisms of neurodegeneration,
transmission
Prion-like propagation of protein misfolding has been implicated in
Alzheimer’s, Parkinson’s and Huntington’s diseases, and the tauopathies.
Amyotrophic lateral sclerosis (ALS) is a common and incurable adult motor neuron
disease, in which mutation of the free-radical defense enzyme superoxide
dismutase 1 (SOD1) is responsible for a subtype of familial ALS (fALS). We
demonstrate that transfection of fALS SOD1 mutants G127X and G85R, as well as
overexpression of non-mutant wild-type (wt) SOD1, can induce misfolding of
natively-structured wild-type SOD1 in human mesenchymal and neural cell lines,
as determined by molecular surface immunoreactivity with misfolding-specific
monoclonal antibodies (mAbs), acquisition of protease sensitivity (suggesting
structural loosening), generation of reactive oxygen species (ROS) and formation
of non-native intermolecular disulfide bonds. Serial transmission of SOD1
misfolding was established by incubation in conditioned media from mtSOD1- or
wtSOD1-transfected HEK cells, and knockdown of endogenous SOD1 expression in HEK
cells by siRNA abrogated the transmission of SOD1 misfolding, consistent with
endogenously expressed SOD1 being the substrate for conformational conversion.
Pre-incubation of SOD1-transfected conditioned media with poly-specific SOD1
antibodies or misfolding-specific mAbs also blocked intercellular transducing
activity, and passive administration of misfolding-specific mAbs extends
survival in the G37R transgenic mouse model of ALS. We conclude that misfolded
SOD1 participates in a template-directed misfolding cascade which provides a
plausable molecular mechanism for progression of familial and sporadic ALS.
Antibody-mediated neutralization of SOD1 misfolding propagation could prove
beneficial in human ALS.
================
Alimentary prion infections: Touch-down in the intestine
Volume 5, Issue 1 January/February/March 2011 Bianca Da Costa Dias,
Katarina Jovanovic and Stefan F.T. Weiss View affiliations Hide affiliations
Bianca Da Costa DiasSchool of Molecular and Cell Biology; University of the
Witwatersrand; Johannesburg, Republic of South Africa Katarina JovanovicSchool
of Molecular and Cell Biology; University of the Witwatersrand; Johannesburg,
Republic of South Africa Stefan F.T. WeissCorresponding author:
stefan.weiss@wits.ac.za School of Molecular and Cell Biology; University of the
Witwatersrand; Johannesburg, Republic of South Africa
Neurodegenerative diseases are caused by proteinaceous aggregates, usually
consisting of misfolded proteins which are often typified by a high proportion
of ß-sheets, which accumulate in the Central Nervous System. These diseases,
including Morbus Alzheimer, Parkinson disease and Transmissible Spongiform
Encephalopathies (TSEs) also termed prion disorders, afflict a substantial
proportion of the human population and as such the etiology and pathogenesis of
these diseases has been the focus of mounting research. Although many of these
diseases arise from genetic mutations or are sporadic in nature, the possible
horizontal transmissibility of neurodegenerative diseases poses a great threat
to population health. In this article we discuss recent studies which suggest
that the “non-transmissible” status bestowed upon Alzheimer and Parkinson
diseases may need to be revised as these diseases have been successfully induced
through tissue transplants. Furthermore, we highlight the importance of
investigating the “natural” mechanism of prion transmission including peroral
and perenteral transmission, proposed routes of gastrointestinal uptake and
neuroinvasion of ingested infectious prion proteins. We examine the multitude of
factors which may influence oral transmissibility and discuss the zoonotic
threats which Chronic Wasting Disease (CWD), Bovine Spongiform Encephalopathy
(BSE) and Scrapie may pose resulting in vCJD or related disorders. In addition,
we suggest that the 37 kDa/67 kDa laminin receptor on the cell surface of
enterocytes, a major cell population in the intestine, may play an important
role in the intestinal pathophysiology of alimentary prion infections.
Commentary ß-amyloid oligomers and prion protein: Fatal attraction?
Volume 5, Issue 1 January/February/March 2011 Gianluigi Forloni and Claudia
Balducci
Gianluigi Forloni Corresponding author: forloni@marionegri.it
Claudia Balducci Biology of Neurodegenerative Diseases Lab; Department of
Neuroscience; “Mario Negri” Institute for Pharmacological Research; Milano,
Italy
The relationship between Alzheimer disease (AD) and prion-related
encephalopathies (TSE) has been proposed by different points of view. Recently,
the scientific attention has been attracted by the results proposing the
possibility that PrPc, the protein whose pathologic form is responsible of TSE,
can mediated the toxic effect of ß amyloid (Aß) oligomers. The oligomers are
considered the culprit of the neurodegenerative process associated to AD,
although the pathogenic mechanism activated by these small aggregates remain to
be elucidated. In the initial study based on the binding screening PrPc was
identified as ligand /receptor of Aß oligomers, while long term potentiation
(LTP) analysis in vitro and behavioural studies in vivo, demonstrated that the
absence of PrPc abolished the damage induced by Aß oligomers. The high affinity
binding Aß oligomers-PrPc has been confirmed, whereas a functional role of this
association has been excluded by three different studies. We approached this
issue by the direct application of Aß oligomers in the brain followed by the
behavioural examination of memory deficits. Our data using PrP knock-out mice
suggest that Aß 1-42 oligomers are responsible for cognitive impairment in AD
but PrPc is not required for their effect. Similarly, in two other studies the
LTP alterations induced by Aß 1-42 oligomers was not influenced by the absence
of PrP. Possible explanations of these contradictory results are
discussed.
Friday, October 22, 2010
Peripherally Applied Aß-Containing Inoculates Induce Cerebral
ß-Amyloidosis
Friday, September 3, 2010
Alzheimer's, Autism, Amyotrophic Lateral Sclerosis, Parkinson's, Prionoids,
Prionpathy, Prionopathy, TSE
Wednesday, January 5, 2011
ENLARGING SPECTRUM OF PRION-LIKE DISEASES Prusiner Colby et al 2011
Prions
David W. Colby1,* and Stanley B. Prusiner1,2
Monday, September 26, 2011
Variably Protease-Sensitive Prionopathy, Prionpathy, Prionopathy, FFI, GSS,
gCJD, hvCJD, sCJD, TSE, PRION, update 2011
Wednesday, October 27, 2010
A novel variant of human disease with a protease-sensitive prion protein
and heterozygosity methionine/valine at codon 129: Case report
snip...
Genetic findings
No mutations were found in the open reading frame after sequencing the
prion protein gene (PRNP). A heterozygosis methionine valine (MV) was observed
in codon 129.
snip...
Thursday, July 10, 2008
A Novel Human Disease with Abnormal Prion Protein Sensitive to Protease
update July 10, 2008
Although several subjects had family histories of dementia, no mutations
were found in the PrP gene open reading frame.
Thursday, July 10, 2008
A New Prionopathy update July 10, 2008
***+++***
Thursday, July 10, 2008
A Novel Human Disease with Abnormal Prion Protein Sensitive to Protease
update July 10, 2008 Friday, June 20, 2008
Here we go folks. AS predicted. THIS JUST OUT !
Tuesday, August 03, 2010
Variably protease-sensitive prionopathy: A new sporadic disease of the
prion protein
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. ...
Wednesday, October 27, 2010
A novel variant of human disease with a protease-sensitive prion protein
and heterozygosity methionine/valine at codon 129: Case report
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
====================================
The familial mutations, Gajdusek proposed, lowered the barrier to such
accidental conversion. "Thus," he wrote in 1996, "with these mutations, this
ordinarily rare event becomes a ... dominant inherited trait." But Weissmann's
qualification still remained to be refuted: the mutations might simply allow
easier entry to a lurking virus. ...page 202 Deadly Feast
===================================
something to think about for sure.
but i interpret this as (1st not the gold standard, just my opinion;-), as
because of certain gene mutations, one or a family, would be more susceptible to
the many different strains of TSE, and the many different proven routes and
sources, (which will cause different symptoms, different incubation periods from
onset of clinical symptoms to death, different parts of the brain infected,
etc.). in other words, it's NOT the gene mutation that CAUSES the disease, but
the fact that it makes you more SUSCEPTIBLE, to the TSEs from the surrounding
environment, and PLUS accumulation, i think this plays a critical role. maybe
there is a one dose scenario, but i think there is more of the 'accumulators'
that go clinical, than the 'one dose'. and what is the threshold to sub-clinical
to clinical ?
anyway, just pondering out loud here.
also, for anyone interested, there are some studies with links to follow
here ;
hmmm, 85%+ of all human TSE prion disease i.e. the infamous sporadic CJD
i.e. is NOT a single strain, but many strains from unknown route and source, and
there has been many of both documented in North America, and no one has ever
proven a spontaneous TSE in any natural field case of any species to date. I
believe they hypothesized one case in a zoo animal at one point, but could never
prove it. please understand too, to date, all iatrogenic CJD is, is sporadic
CJD, until route and source is proven.
spontaneous TSE, or just another excuse of a name for the same disease i.e.
TSE prion disease ;
Prions: Protein Aggregation and Infectious Diseases
ADRIANO AGUZZI AND ANNA MARIA CALELLA
Institute of Neuropathology, University Hospital of Zurich, Zurich,
Switzerland
snip...
3. Sporadic Creutzfeldt-Jakob disease Approximately 85% of all human prion
diseases are sporadic forms of CJD. For sCJD, there is no association with a
mutant PRNP allele, nor is there any epidemiological evidence for exposure to a
TSE agent through contact with people or animals infected with TSEs. sCJD cases
are currently subclassified according to the methionine/valine polymorphism at
codon 129 of the PRNP gene and the size and glycoform ratio of proteaseresistant
prion protein identified on western blot (type 1 or type 2) (174).
Heterozygosity (Met/Val) at PrP codon 129 appears to be associated with a lower
risk (378) and/or prolonged incubation time (119, 387). The lack of routine
laboratory testing for preclinical diagnosis makes the search for agent sources
and other risk factors extremely difficult. At present, the means of acquisition
of a TSE agent in these patients remains a mystery. *** So far, there is no
evidence for spontaneous PrPSc formation in any animal or human TSE. In humans,
the peak age incidence of sporadic CJD is 55-60 years. However, if spontaneous
misfolding were the primary event, one might expect a continuously increasing
incidence with age because more time would allow more opportunity for rare
misfolding events.
snip...
*** So far, there is no evidence for spontaneous PrPSc formation in any
animal or human TSE. In humans, the peak age incidence of sporadic CJD is 55–60
years. However, if spontaneous misfolding were the primary event, one might
expect a continuously increasing incidence with age because more time would
allow more opportunity for rare misfolding events.
*** So far, there is no evidence for spontaneous PrPres formation in any
animal or human TSE disease. Moreover, in New Zealand and Australia where
scrapie has been eradicated, there is no evidence of spontaneous occurrence of
sheep scrapie. In addition, in humans the peak age incidence of sporadic CJD is
55–60 years, and if spontaneous misfolding were the primary event, one might
expect a continuously increasing incidence with age, since more time might allow
more opportunity for rare misfolding events.
*** However, a BSE expert said that consumption of infected material is the
only known way that cattle get the disease under natural conditons.
“In view of what we know about BSE after almost 20 years experience,
contaminated feed has been the source of the epidemic,” said Paul Brown, a
scientist retired from the National Institute of Neurological Diseases and
Stroke.
BSE is not caused by a microbe. It is caused by the misfolding of the
so-called “prion protein” that is a normal constituent of brain and other
tissues. If a diseased version of the protein enters the brain somehow, it can
slowly cause all the normal versions to become misfolded. It is possible the
disease could arise spontaneously, though such an event has never been recorded,
Brown said.
*** Conclusion/Significance: Our results point to a possibly higher degree
of pathogenicity of BASE than classical BSE in primates and also raise a
question about a possible link to one uncommon subset of cases of apparently
sporadic CJD. Thus, despite the waning epidemic of classical BSE, the occurrence
of atypical strains should temper the urge to relax measures currently in place
to protect public health from accidental contamination by BSE-contaminated
products.
SPONTANEOUS TSE
Perspectives BIOMEDICINE: A Fresh Look at BSE Bruce Chesebro*
Mad cow disease, or bovine spongiform encephalopathy (BSE), is the cattle
form of a family of progressive brain diseases. These diseases include scrapie
in sheep, Creutzfeldt-Jakob disease (CJD) in humans, and chronic wasting disease
(CWD) in deer and elk. They are also known as either "prion diseases" because of
the association of a misfolded cellular prion protein in pathogenesis or
"transmissible spongiform encephalopathies" (TSEs) because of the spongelike
nature of the damaged brain tissue (1).
The recent discovery of two BSE-infected cows, one in Canada and one in the
United States, has dramatically increased concern in North America among meat
producers and consumers alike over the extent to which BSE poses a threat to
humans as well as to domestic and wild animals. The European BSE epidemic of the
late-1980s seems to have been initiated a decade earlier in the United Kingdom
by changes in the production of meat and bone meal (MBM) from rendered
livestock, which led to contamination of MBM with the BSE infectious agent.
Furthermore, the fact that UK farmers fed this rendered MBM to younger animals
and that this MBM was distributed to many countries may have contributed to the
ensuing BSE epidemic in the United Kingdom and internationally (2).
Despite extensive knowledge about the spread of BSE through contaminated
MBM, the source of BSE in Europe remains an unsolved mystery (2). It has been
proposed that BSE could be derived from a cross-species infection, perhaps
through contamination of MBM by scrapie-infected sheep tissues (see the figure).
Alternatively, BSE may have been an endemic disease in cattle that went
unnoticed because of its low level of horizontal transmission. Lastly, BSE might
have originated by "spontaneous" misfolding of the normal cellular prion protein
into the disease-associated abnormal isoform (3), which is postulated to be the
infectious agent or "prion."
Five possible sources of BSE in North American cattle. Sheep, deer, and elk
could spread prion diseases (TSEs) to cattle through direct animal contact or
contamination of pastures. Endemic BSE has not been proven to exist anywhere in
the world, but it is difficult to exclude this possibility because of the
inefficient spread of BSE infectivity between individual animals (2). ___BSE
caused by spontaneous misfolding of the prion protein has not been proven___.
CREDIT: KATHARINE SUTLIFF/SCIENCE
snip...
Nevertheless, the idea that BSE might originate due to the spontaneous
misfolding of prion proteins has received renewed interest in the wake of
reports suggesting the occurrence of atypical BSE (9-11). These results imply
that new strains of cattle BSE might have originated separately from the main UK
outbreak. Where and how might such strains have originated? Although such rare
events cannot be studied directly, any number of sources of the original BSE
strain could also explain the discovery of additional BSE strains in cattle (see
the figure). However, it would be worrisome if spontaneous BSE were really a
valid etiology because such a mechanism would be impossible to prevent--unlike
other possible scenarios that could be controlled by large-scale eradication of
TSE-positive animals.
Another way to look at this problem is to examine evidence for possible
spontaneous TSE disease in other animals besides cattle. Spontaneous BSE would
be extremely difficult to detect in cattle, where horizontal spread is minimal.
However, in the case of the sheep TSE disease, scrapie, which spreads from ewes
to lambs at birth as well as between adults, spontaneous disease should be
detectable as new foci of clinical infection. In the early 1950s scrapie was
eradicated in both Australia and New Zealand, and the mainland of both these
countries has remained scrapie-free ever since. This scrapie-free status is not
the result of selection of sheep resistant to scrapie because sheep from New
Zealand are as susceptible as their UK counterparts to experimental scrapie
infection (12). These experiments of man and nature appear to indicate that
spontaneous clinical scrapie does not occur in sheep. Similarly, because CWD is
known to spread horizontally, the lack of CWD in the deer or elk of eastern
North America but its presence in western regions would also argue against a
spontaneous disease mechanism. This is particularly noteworthy in New Zealand,
where there are large numbers of deer and elk farms and yet no evidence of
spontaneous CWD. If spontaneous scrapie does not occur in sheep or deer, this
would suggest that spontaneous forms of BSE and sporadic Creutzfeldt-Jakob
disease (sCJD) are unlikely to be found in cattle or humans. The main caveat to
this notion is that spontaneous disease may arise in some animal species but not
others. In humans, sCJD--which is considered by some researchers to begin by
spontaneous misfolding of the prion protein--usually takes more than 50 years to
appear. Thus, in animals with a shorter life-span, such as sheep, deer, and
cattle, an analogous disease mechanism might not have time to develop.
What can we conclude so far about BSE in North America? Is the BSE detected
in two North American cows sporadic or spontaneous or both? "Sporadic" pertains
to the rarity of disease occurrence. "Spontaneous" pertains to a possible
mechanism of origin of the disease. These are not equivalent terms. The rarity
of BSE in North America qualifies it as a sporadic disease, but this low
incidence does not provide information about cause. For the two reported North
American BSE cases, exposure to contaminated MBM remains the most likely
culprit. However, other mechanisms are still possible, including cross-infection
by sheep with scrapie or cervids with CWD, horizontal transmission from cattle
with endemic BSE, and spontaneous disease in individual cattle. Based on our
understanding of other TSEs, the spontaneous mechanism is probably the least
likely. Thus, "idiopathic" BSE--that is, BSE of unknown etiology--might be a
better term to describe the origin of this malady. ...
snip...full text ;
DR. DEHAVEN: “All right. I think we've got three different questions in
there, and I'll try to touch on each one of them.
“First of all, let me correct just a technical issue, and that is you
mentioned 1 in 10,000. And actually our surveillance system currently is
designed, the one that we have in place now is designed to detect 1 positive in
1 million cattle, and I gave some numbers between 200,000 and 268,000 that would
allow us to detect 1 in 10 million as opposed to 1 in 10,000.
“So we would, if we were able to collect in the ballpark of those numbers
of samples then we with increasing numbers of samples have an increasingly
statistically valid sample from which to determine, one, whether or not the
disease exists and, if so, at what prevalence level.
“So our real emphasis is to test as many of those animals as we can, ensure
that we get an appropriate geographical distribution, but not setting a specific
number as far as a target. Again, consistent with the recommendation from the
International Review Team, their recommendation was to test all of them.
“So that's consistent with where we're going is to test as many as we
possibly can.
*** “As far as spontaneous cases, that is a very difficult issue.
**___There is no evidence to prove that spontaneous BSE occurs in cattle___; but
here again it's an issue of proving a negative. We do know that CJD, the human
version of the disease, does occur spontaneously in humans at the rate of about
1 in 1 million. We don't have enough data to definitively say that spontaneous
cases of BSE in cattle occur or do not occur.
“Again, it's a very difficult situation to prove a negative.
“So a lot of research is ongoing. Certainly if we do come up with any
positive samples in the course of this surveillance we will be looking at that
question in evaluating those samples but no scientifically hard evidence to
confirm or refute whether or not spontaneous cases of BSE occur.
snip...
Thursday, June 21, 2012
Clinical and Pathologic Features of H-Type Bovine Spongiform Encephalopathy
Associated with E211K Prion Protein Polymorphism
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)
PrPSc complexity in different forms of Creutzfeldt-Jakob disease identified
using biochemical approaches
Young Pyo Choi Doctor of Philosophy University of Edinburgh 2010
Abstract Transmissible spongiform encephalopathies (TSEs) or prion
diseases are a group of fatal neurodegenerative diseases affecting humans and
animal species. Prion diseases are characterized by the conversion of the host
encoded prion protein (PrPC) into a disease-associated isoform (PrPSc), which
(according to the prion hypothesis) is thought to be the main component of the
infectious agent. PrPSc has been traditionally distinguished from PrPC by its
biochemical properties, such as partial resistance to proteolysis and
detergent-insolubility. In the absence of a foreign nucleic acid genome
associated with prion diseases, efforts to provide a molecular basis for the
biological diversity of prions have focused on biochemical characterization of
PrPSc. In Creutzfeldt-Jakob disease (CJD) and other forms of human prion
disease, the biochemical characterization of PrPSc has been largely restricted
to the analysis of PK-resistant fragments of PrPSc (PrPres) by Western blot.
However, given recent findings on the complexity of PrPSc identified in
laboratory prion strains, PrPres analysis alone may not provide a complete
description of PrPSc present in CJD brains. For a more complete characterization
of PrPSc in human prion diseases, this study investigated biochemical properties
of PrPSc in different forms of CJD by employing approaches that differ in
principle from conventional Western blot analysis of PrPres. The novel
biochemical approaches used in this study have identified further complexity of
PrPSc accumulated in CJD brains, not only between different forms of CJD but
also within single cases of individual disease entities. In this study, the two
biochemical criteria most frequently used to define PrPSc (3F4 epitope
accessibility versus resistance to limited proteolysis) did not always
correlate, indicating probable non-uniform distribution of PK-sensitive isoform
of PrPSc within the same CJD brains. In variant CJD (vCJD) brains, the thalamic
region, which is characterized by distinct neuropathological features, could
also be distinguished from frontal cortex and cerebellum by the sedimentation
profiles of PrPC and PrPSc on sucrose step gradients. Moreover, the
conformational stability of PrPSc was found not to be uniform among human prion
diseases and did not correlate with PrPres type or v prion protein genotype.
Taken together, the results from this study provide a more complete description
of PrPSc species occurring in CJD brains and contribute to a fuller
understanding of the agents and the disease processes involved in humans.
snip...
The high susceptibility of PrPC molecules present in non-CJD brains to PK
was also observed in a recent study reporting "protease-sensitive prionpathy"
cases (Gambetti et al. 2008), in which PrPC molecules became undetectable
following treatment even with 1μg/ml PK for 1 hour at 37°C.
SNIP...
In another study describing a novel human prion disease designated
"proteasesensitive prionpathy" (or PSPr), the sedimentation profile of PrP from
this novel prion disease was different from any of this study's in that quite
low levels of PrP were distributed in the intermediate and bottom fractions
(Gambetti et al. 2008);
interestingly, the result from GSS with A117V mutation was similar to that
of PSPr. In laboratory prion strains such as ME7, 22L in mice or Sc237 in
hamsters, PrP dispersed throughout the 10 - 60% gradient after
ultracentrifugation (Pan et al. 2004; Pan et al. 2005a; Pan et al. 2005c; Tzaban
et al. 2002). The results from these laboratory prion stains were quite similar
to those from vCJD Th or FC of MM1 sCJD.
SNIP...
5.3 Implications of this study
The accumulation of PrPSc is the only unambiguous marker of prion infection
established to date and PrPSc is the only known component of the infectious
prions. PrPSc has been operationally defined by its biochemical properties such
as insolubility in non-denaturing detergents and/or resistance to proteolytic
degradation (Meyer et al. 1986). The property of PK-resistance has been
thoroughly exploited to the extent that the terms of protease-resistant prion
protein (PrPres) and diseaseassociated prion protein (PrPSc) are sometimes used
interchangeably (Caughey et al. 2009). In the absence of a foreign nucleic acid
genome associated with prion diseases, the strain phenomenon in prion diseases
has been explained by the conformational difference of PrPSc according to the
prion hypothesis (Prusiner 1998). Efforts to provide a molecular basis for the
biological diversity of prions have focused on biochemical characterization of
PrPSc. In human prion diseases including CJD, much evidence supporting
conformation-based strain diversity has been gathered by Western blot analysis
of PrPres. Such assays produce information on core fragment size and
glycosylation site occupancy of PrPres. Variation in these parameters in
combination with PRNP genotype has been invoked as the molecular basis to
distinguish different disease phenotypes (Hill et al. 2003; Parchi et al. 1999b;
Parchi et al. 1996). Considering recent findings on the complexity of PrPSc
largely identified in laboratory prion strains, however, PrPres analysis alone
may not provide a complete description of PrPSc present in CJD brains. In that
context, this study identifies previously unrecognised heterogeneity in PrPSc in
CJD brains through the use of assays that differ in principle from conventional
Western blot analysis of PrPres. The novel biochemical approaches employed in
this study have identified complexity of PrPSc in CJD brains, not only between
different forms of human prion disease but also within individual cases of
particular disease entities. Moreover, recent studies have reported that
biochemical parameters such as PrPres stability and the size of PrPres
aggregates can have significant effects on the biological properties of prions
(Colby et al. 2009; Legname et al. 2006; Silveira et al. 2005). Therefore, the
results from this study not only provide a more complete description of
PrPSc
235
species occurring in CJD but also would contribute to a fuller
understanding of the agents that cause the disease in humans. Understanding how
the PrPSc complexity newly recognized in this study relates with the disease
phenotypes and/or prion strains remains to be determined.
Wednesday, March 31, 2010
Atypical BSE in Cattle
To date the OIE/WAHO assumes that the human and animal health standards set
out in the BSE chapter for classical BSE (C-Type) applies to all forms of BSE
which include the H-type and L-type atypical forms. This assumption is
scientifically not completely justified and accumulating evidence suggests that
this may in fact not be the case. Molecular characterization and the spatial
distribution pattern of histopathologic lesions and immunohistochemistry (IHC)
signals are used to identify and characterize atypical BSE. Both the L-type and
H-type atypical cases display significant differences in the conformation and
spatial accumulation of the disease associated prion protein (PrPSc) in brains
of afflicted cattle. Transmission studies in bovine transgenic and wild type
mouse models support that the atypical BSE types might be unique strains because
they have different incubation times and lesion profiles when compared to C-type
BSE.
When L-type BSE was inoculated into ovine transgenic mice and Syrian
hamster the resulting molecular fingerprint had changed, either in the first or
a subsequent passage, from L-type into C-type BSE. In addition, non-human
primates are specifically susceptible for atypical BSE as demonstrated by an
approximately 50% shortened incubation time for L-type BSE as compared to
C-type. Considering the current scientific information available, it cannot be
assumed that these different BSE types pose the same human health risks as
C-type BSE or that these risks are mitigated by the same protective
measures.
This study will contribute to a correct definition of specified risk
material (SRM) in atypical BSE. The incumbent of this position will develop new
and transfer existing, ultra-sensitive methods for the detection of atypical BSE
in tissue of experimentally infected cattle.
Thursday, August 12, 2010
Seven main threats for the future linked to prions
First threat
The TSE road map defining the evolution of European policy for protection
against prion diseases is based on a certain numbers of hypotheses some of which
may turn out to be erroneous. In particular, a form of BSE (called atypical
Bovine Spongiform Encephalopathy), recently identified by systematic testing in
aged cattle without clinical signs, may be the origin of classical BSE and thus
potentially constitute a reservoir, which may be impossible to eradicate if a
sporadic origin is confirmed.
***Also, a link is suspected between atypical BSE and some apparently
sporadic cases of Creutzfeldt-Jakob disease in humans. These atypical BSE cases
constitute an unforeseen first threat that could sharply modify the European
approach to prion diseases.
Second threat
snip...
Rural and Regional Affairs and Transport References Committee
The possible impacts and consequences for public health, trade and
agriculture of the Government's decision to relax import restrictions on beef
Final report June 2010
2.65 At its hearing on 14 May 2010, the committee heard evidence from Dr
Alan Fahey who has recently submitted a thesis on the clinical neuropsychiatric,
epidemiological and diagnostic features of Creutzfeldt-Jakob disease.48 Dr Fahey
told the committee of his concerns regarding the lengthy incubation period for
transmissible spongiform encephalopathies, the inadequacy of current tests and
the limited nature of our current understanding of this group of
diseases.49
2.66 Dr Fahey also told the committee that in the last two years a link has
been established between forms of atypical CJD and atypical BSE. Dr Fahey said
that: They now believe that those atypical BSEs overseas are in fact causing
sporadic Creutzfeldt-Jakob disease. They were not sure if it was due to mad
sheep disease or a different form. If you look in the textbooks it looks like
this is just arising by itself. But in my research I have a summary of a
document which states that there has never been any proof that sporadic
Creutzfeldt-Jakob disease has arisen de novo-has arisen of itself. There is no
proof of that. The recent research is that in fact it is due to atypical forms
of mad cow disease which have been found across Europe, have been found in
America and have been found in Asia. These atypical forms of mad cow disease
typically have even longer incubation periods than the classical mad cow
disease.50
14th ICID International Scientific Exchange Brochure -
Final Abstract Number: ISE.114
Session: International Scientific Exchange
Transmissible Spongiform encephalopathy (TSE) animal and human TSE in North
America update October 2009
T. Singeltary
Bacliff, TX, USA
Background:
An update on atypical BSE and other TSE in North America. Please remember,
the typical U.K. c-BSE, the atypical l-BSE (BASE), and h-BSE have all been
documented in North America, along with the typical scrapie's, and atypical
Nor-98 Scrapie, and to date, 2 different strains of CWD, and also TME. All these
TSE in different species have been rendered and fed to food producing animals
for humans and animals in North America (TSE in cats and dogs ?), and that the
trading of these TSEs via animals and products via the USA and Canada has been
immense over the years, decades.
Methods:
12 years independent research of available data
Results:
I propose that the current diagnostic criteria for human TSEs only enhances
and helps the spreading of human TSE from the continued belief of the UKBSEnvCJD
only theory in 2009. With all the science to date refuting it, to continue to
validate this old myth, will only spread this TSE agent through a multitude of
potential routes and sources i.e. consumption, medical i.e., surgical, blood,
dental, endoscopy, optical, nutritional supplements, cosmetics etc.
Conclusion:
I would like to submit a review of past CJD surveillance in the USA, and
the urgent need to make all human TSE in the USA a reportable disease, in every
state, of every age group, and to make this mandatory immediately without
further delay. The ramifications of not doing so will only allow this agent to
spread further in the medical, dental, surgical arena's. Restricting the
reporting of CJD and or any human TSE is NOT scientific. Iatrogenic CJD knows NO
age group, TSE knows no boundaries. I propose as with Aguzzi, Asante, Collinge,
Caughey, Deslys, Dormont, Gibbs, Gajdusek, Ironside, Manuelidis, Marsh, et al
and many more, that the world of TSE Transmissible Spongiform Encephalopathy is
far from an exact science, but there is enough proven science to date that this
myth should be put to rest once and for all, and that we move forward with a new
classification for human and animal TSE that would properly identify the
infected species, the source species, and then the route.
Monday, May 23, 2011
Atypical Prion Diseases in Humans and Animals 2011
Top Curr Chem (2011)
DOI: 10.1007/128_2011_161
# Springer-Verlag Berlin Heidelberg 2011
Michael A. Tranulis, Sylvie L. Benestad, Thierry Baron, and Hans
Kretzschmar
Abstract
Although prion diseases, such as Creutzfeldt-Jakob disease (CJD) in humans
and scrapie in sheep, have long been recognized, our understanding of their
epidemiology and pathogenesis is still in its early stages. Progress is hampered
by the lengthy incubation periods and the lack of effective ways of monitoring
and characterizing these agents. Protease-resistant conformers of the prion
protein (PrP), known as the "scrapie form" (PrPSc), are used as disease markers,
and for taxonomic purposes, in correlation with clinical, pathological, and
genetic data. In humans, prion diseases can arise sporadically (sCJD) or
genetically (gCJD and others), caused by mutations in the PrP-gene (PRNP), or as
a foodborne infection, with the agent of bovine spongiform encephalopathy (BSE)
causing variant CJD (vCJD). Person-to-person spread of human prion disease has
only been known to occur following cannibalism (kuru disease in Papua New
Guinea) or through medical or surgical treatment (iatrogenic CJD, iCJD). In
contrast, scrapie in small ruminants and chronic wasting disease (CWD) in
cervids behave as infectious diseases within these species. Recently, however,
so-called atypical forms of prion diseases have been discovered in sheep
(atypical/Nor98 scrapie) and in cattle, BSE-H and BSE-L. These maladies resemble
sporadic or genetic human prion diseases and might be their animal equivalents.
This hypothesis also raises the significant public health question of possible
epidemiological links between these diseases and their counterparts in
humans.
M.A. Tranulis (*)
Norwegian School of Veterinary Science, Oslo, Norway
e-mail: Michael.Tranulis@nvh.no
S.L. Benestad
Norwegian Veterinary Institute, Oslo, Norway
T. Baron
Agence Nationale de Se´curite´ Sanitaire, ANSES, Lyon, France
H. Kretzschmar
Ludwig-Maximilians University of Munich, Munich, Germany
Keywords Animal Atypical Atypical/Nor98 scrapie BSE-H BSE-L Human Prion
disease Prion strain Prion type
snip...SEE MORE HERE ;
Saturday, June 25, 2011
Transmissibility of BSE-L and Cattle-Adapted TME Prion Strain to Cynomolgus
Macaque
"BSE-L in North America may have existed for decades"
Over the next 8-10 weeks, approximately 40% of all the adult mink on the
farm died from TME.
snip...
The rancher was a ''dead stock'' feeder using mostly (>95%) downer or
dead dairy cattle...
Wednesday, April 24, 2013
Dissociation between Transmissible Spongiform Encephalopathy (TSE)
Infectivity and Proteinase K-Resistant PrPSc Levels in Peripheral Tissue from a
Murine Transgenic Model of TSE Disease
Saturday, December 15, 2012
Bovine spongiform encephalopathy: the effect of oral exposure dose on
attack rate and incubation period in cattle -- an update 5 December 2012
Friday, April 19, 2013
FDA BSE TSE PRION NEWS FEED AND ANNUAL INSPECTION OF FEED MILLS REPORTS HAS
CEASED TO EXIST
Monday, March 25, 2013
Minnesota Firm Recalls Bone-In Ribeye That May Contain Specified Risk
Materials Recall Release CLASS II RECALL FSIS-RC-024-2013
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
Wednesday, March 20, 2013
GAO-13-244, Mar 18, 2013 Dietary Supplements FDA May Have Opportunities to
Expand Its Use of Reported Health Problems to Oversee Product
From: Terry S. Singeltary Sr.
Sent: Tuesday, March 19, 2013 2:46 PM
To: gomezj@gao.gov
Cc: siggerudk@gao.gov ; youngc1@gao.gov ; oighotline@gao.gov
Wednesday, February 20, 2013
World Organization for Animal Health Recommends United States' BSE Risk
Status Be Upgraded
Statement from Agriculture Secretary Tom Vilsack:
Thursday, February 14, 2013
The Many Faces of Mad Cow Disease Bovine Spongiform Encephalopathy BSE and
TSE prion disease
Friday, April 19, 2013
Bovine Spongiform Encephalopathy (BSE) Feed Safety Support Program Grants
Fiscal Year 2011: October 1, 2010 - September 30, 2011 FDA
Friday, April 19, 2013
APHIS 2013 Stakeholder Meeting (March 2013) BSE TSE PRION
Tuesday, April 30, 2013
Mad cow infected blood 'to kill 1,000’
Wednesday, April 24, 2013
Chimpanzees Released After 30 Years Of Testing, Brace Yourself For Smiles
Tuesday, April 30, 2013
Foodborne Transmission of Bovine Spongiform Encephalopathy to Nonhuman
Primates
Friday, November 23, 2012
sporadic Creutzfeldt-Jakob Disease update As at 5th November 2012 UK, USA,
AND CANADA
Sunday, December 2, 2012
CANADA 19 cases of mad cow disease SCENARIO 4: ‘WE HAD OUR CHANCE AND WE
BLEW IT’
Thursday, February 21, 2013
National Prion Disease Pathology Surveillance Center Cases Examined January
16, 2013
16 YEAR OLD SPORADIC FFI ?
Monday, January 14, 2013
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
Monday, December 31, 2012
Creutzfeldt Jakob Disease and Human TSE Prion Disease in Washington State,
2006–2011-2012
Tuesday, December 25, 2012
CREUTZFELDT JAKOB TSE PRION DISEASE HUMANS END OF YEAR REVIEW DECEMBER 25,
2012
Tuesday, June 26, 2012
Creutzfeldt Jakob Disease Human TSE report update North America, Canada,
Mexico, and USDA PRION UNIT as of May 18, 2012
type determination pending Creutzfeldt Jakob Disease (tdpCJD), is on the
rise in Canada and the USA
Wednesday, June 13, 2012
MEXICO IS UNDER or MIS DIAGNOSING CREUTZFELDT JAKOB DISEASE AND OTHER PRION
DISEASE SOME WITH POSSIBLE nvCJD
*** 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 $
Sunday, March 31, 2013
Creutzfeldt Jakob Disease CJD worlds youngest documented victim, 11 years
old, shall we pray
Monday, April 15, 2013
Dr. Stephen B. Thacker Director Centers for Disease Control and
Prevention′s Office of Science, Epidemiology and Laboratory Services (OSELS)
dies from Creutzfeldt Jakob Disease CJD
Tuesday, March 19, 2013
Alzheimer's Association 2013 Alzheimer's Disease Facts and Figures
Today, an American develops Alzheimer's disease every 68 seconds. In 2050,
an American will develop the disease every 33 seconds.
Wednesday, May 16, 2012
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion
disease, Iatrogenic, what if ?
Proposal ID: 29403
Wednesday, September 21, 2011
PrioNet Canada researchers in Vancouver confirm prion-like properties in
Amyotrophic Lateral Sclerosis (ALS)
Sunday, February 10, 2013
Parkinson's Disease and Alpha Synuclein: Is Parkinson's Disease a
Prion-Like Disorder?
Ann N Y Acad Sci. 1982;396:131-43.
Alzheimer's disease and transmissible virus dementia (Creutzfeldt-Jakob
disease).
Brown P, Salazar AM, Gibbs CJ Jr, Gajdusek DC.
Abstract
Ample justification exists on clinical, pathologic, and biologic grounds
for considering a similar pathogenesis for AD and the spongiform virus
encephalopathies. However, the crux of the comparison rests squarely on results
of attempts to transmit AD to experimental animals, and these results have not
as yet validated a common etiology. Investigations of the biologic similarities
between AD and the spongiform virus encephalopathies proceed in several
laboratories, and our own observation of inoculated animals will be continued in
the hope that incubation periods for AD may be even longer than those of CJD.
CJD1/9 0185 Ref: 1M51A
IN STRICT CONFIDENCE
Dr McGovern From: Dr A Wight Date: 5 January 1993 Copies: Dr Metters Dr
Skinner Dr Pickles Dr Morris Mr Murray
TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES
1. CMO will wish to be aware that a meeting was held at DH yesterday, 4
January, to discuss the above findings. It was chaired by Professor Murray
(Chairman of the MRC Co-ordinating Committee on Research in the Spongiform
Encephalopathies in Man), and attended by relevant experts in the fields of
Neurology, Neuropathology, molecular biology, amyloid biochemistry, and the
spongiform encephalopathies, and by representatives of the MRC and AFRC. 2.
Briefly, the meeting agreed that:
i) Dr Ridley et als findings of experimental induction of p amyloid in
primates were valid, interesting and a significant advance in the understanding
of neurodegenerative disorders;
ii) there were no immediate implications for the public health, and no
further safeguards were thought to be necessary at present; and
iii) additional research was desirable, both epidemiological and at the
molecular level. Possible avenues are being followed up by DH and the MRC, but
the details will require further discussion. 93/01.05/4.1
BSE101/1 0136
IN CONFIDENCE
5 NOV 1992 CMO From: Dr J S Metters DCMO 4 November 1992
TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES
1. Thank you for showing me Diana Dunstan's letter. I am glad that MRC have
recognized the public sensitivity of these findings and intend to report them in
their proper context. This hopefully will avoid misunderstanding and possible
distortion by the media to portray the results as having more greater
significance than the findings so far justify.
2. Using a highly unusual route of transmission (intra-cerebral injection)
the researchers have demonstrated the transmission of a pathological process
from two cases one of severe Alzheimer's disease the other of
Gerstmann-Straussler disease to marmosets. However they have not demonstrated
the transmission of either clinical condition as the "animals were behaving
normally when killed'. As the report emphasizes the unanswered question is
whether the disease condition would have revealed itself if the marmosets had
lived longer. They are planning further research to see if the conditions, as
opposed to the partial pathological process, is transmissible. What are the
implications for public health?
3. The route of transmission is very specific and in the natural state of
things highly unusual. However it could be argued that the results reveal a
potential risk, in that brain tissue from these two patients has been shown to
transmit a pathological process. Should therefore brain tissue from such cases
be regarded as potentially infective? Pathologists, morticians, neuro surgeons
and those assisting at neuro surgical procedures and others coming into contact
with "raw" human brain tissue could in theory be at risk. However, on a priori
grounds given the highly specific route of transmission in these experiments
that risk must be negligible if the usual precautions for handling brain tissue
are observed.
92/11.4/1-1 BSE101/1 0137
4. The other dimension to consider is the public reaction. To some extent
the GSS case demonstrates little more than the transmission of BSE to a pig by
intra-cerebral injection. If other prion diseases can be transmitted in this way
it is little surprise that some pathological findings observed in GSS were also
transmissible to a marmoset. But the transmission of features of Alzheimer's
pathology is a different matter, given the much greater frequency of this
disease and raises the unanswered question whether some cases are the result of
a transmissible prion. The only tenable public line will be that "more research
is required" before that hypothesis could be evaluated. The possibility on a
transmissible prion remains open. In the meantime MRC needs carefully to
consider the range and sequence of studies needed to follow through from the
preliminary observations in these two cases. Not a particularly comfortable
message, but until we know more about the causation of Alzheimer's disease the
total reassurance is not practical.
JS METTERS Room 509 Richmond House Pager No: 081-884 3344 Callsign: DOH 832
121/YdeS 92/11.4/1.2
BSE101/1 0136
IN CONFIDENCE
CMO
From: Dr J S Metters DCMO
4 November 1992
TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES
CJD1/9 0185
Ref: 1M51A
IN STRICT CONFIDENCE
From: Dr. A Wight Date: 5 January 1993
Copies:
Dr Metters Dr Skinner Dr Pickles Dr Morris Mr Murray
TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES
Thursday, August 4, 2011
Terry Singeltary Sr. on the Creutzfeldt-Jakob Disease Public Health Crisis,
Date aired: 27 Jun 2011 (SEE VIDEO)
TSS