Synucleinopathies: Past, Present and Future
Article Type: Editorial
Synucleinopathies: Past, Present and Future
Maria Grazia Spillantini1 and Michel Goedert2
1 Department of Clinical Neurosciences, University of Cambridge, Cambridge,
UK
2 MRC Laboratory of Molecular Biology, Cambridge, UK Please send
correspondence to MGS (mgs11@cam.ac.uk) or MG (mg@mrc-lmb.cam.ac.uk)
Parkinson’s disease (PD), PD dementia (PDD), dementia with Lewy bodies
(DLB) and multiple system atrophy (MSA) are the most common synucleinopathies.
The ordered assembly of α-synuclein leading from a soluble, lipid-bound, to an
insoluble, filamentous protein underlies these disorders. Fibrils formed from
α-synuclein (Lewy pathology) are seen in brain neurons of more than 95% of
patients with PD, and their formation is associated with neurodegeneration.
Missense mutations in SNCA, the α-synuclein gene, and multiplications thereof,
cause rare cases of PD. Two missense mutations (G51D and A53E) can give rise to
neuropathological features reminiscent of both PD and MSA. Sequence variants in
the regulatory region of SNCA are associated with increased disease risk.
Overexpression of human mutant α-synuclein in animal models causes its ordered
assembly and neurodegeneration.
α-Synuclein is a 140 amino acid protein that is concentrated in nerve
terminals. It binds to lipids through its amino-terminal half, which comprises
seven imperfect repeats, and takes on a partly α-helical structure. Under
pathological conditions, α-synuclein self assembles into β-sheet-rich oligomers
and fibrils. They assemble from the full-length protein, but only approximately
amino acids 30-100 make up the structured part. The related lipid-binding
proteins β-synuclein and γ- synuclein are not found in the pathological
inclusions of synucleinopathies. Moreover, mouse lines knockout for α-synuclein
do not develop neurodegeneration. It follows that synucleinopathies are gain of
toxic function, not loss of function, diseases, with the ordered assembly of α-
synuclein constituting the gain of toxic function.
Close to 200 years ago, James Parkinson published his 1817 monograph
entitled “An Essay on the Shaking Palsy”, in which he reported the first
detailed clinical description of the disease that Jean- Martin Charcot named
after him in 1872. In 1912, Fritz Heinrich Lewy described the inclusions that
characterise PD, PDD and DLB in the dorsal motor nucleus of the vagus nerve, the
basal nucleus of Meynert, the globus pallidus and the thalamus. In 1919,
Konstantin Tretiakoff reported the presence of what he called “corps de Lewy”
(Lewy bodies) in the substantia nigra. He also showed degeneration of the
substantia nigra in PD and postulated a connection between nerve cell loss,
rigidity and tremor. This discovery followed work by Paul Blocq and Georges
Marinesco, who reported a case of parkinsonian tremor caused by a tumour of the
substantia nigra. α-Synuclein came to the fore in 1997, when the first genetic
cause of PD was identified and the presence of α- synuclein in Lewy bodies and
neurites was established in sporadic PD and DLB. The following year, α-synuclein
was also shown to be the major component of the filamentous inclusions of MSA
(Papp-Lantos bodies).
In this special issue of Neuropathology and Applied Neurobiology on
synucleinopathies, leading investigators provide an overview of this vibrating
field. A basic understanding is at hand and it appears increasingly likely that
safe and effective mechanism-based therapies for synucleinopathies will be
developed. They will probably be aimed at prevention rather than at treating
already existing disease. PD stands out among neurodegenerative diseases, in
that an effective symptomatic therapy in the form of dopamine replacement
already exists. In the first contribution, Roger Barker and Caroline
Williams-Gray provide a comprehensive overview of the clinical features of PD
and compare them with those of other synucleinopathies (1). In the second
article, Nadia Stefanova and Gregor Wenning focus on the rarer, but more
aggressive, MSA, which is divided into parkinsonian (MSA-P) and cerebellar
(MSA-C) forms, with many cases having features of both (mixed-type MSA) (2).
Autonomic dysfunction is a major feature of MSA. Atypical MSA defines cases of
MSA-P and MSA-C that also have frontotemporal dementia, in the apparent absence
of autonomic dysfunction. Pathologically, glial cytoplasmic inclusions, besides
neuronal inclusions, distinguish MSA from PD, PDD and DLB, where the
α-synuclein-positive Lewy pathology is mostly neuronal. It remains to be seen if
distinct strains of aggregated α- synuclein give rise to these pathologies. Two
silver staining methods, Gallyas-Braak and Campbell-Switzer, distinguish between
the α-synuclein inclusions of MSA and PD. The inclusions of MSA are positive
with both stains, whereas those of PD are negative with Gallyas-Braak.
Clinically, PD and MSA are primarily movement disorders. Nerve cell loss in the
pars compacta of the substantia nigra associated with Lewy pathology is the
major hallmark of sporadic PD, which is often preceded by non-motor prodromal
signs, such as hyposmia, constipation, depression and sleep disorders.
Significant cognitive dysfunction is associated more often with PD than with
MSA.
The prodromal stages of PD may reflect the presence of Lewy pathology
outside the substantia nigra. Based on cross-sectional neuroanatomical studies
of the presence of Lewy pathology, Braak, Del Tredici and colleagues have
suggested that the disease process may start in the gastrointestinal tract,
sympathetic ganglia and olfactory bulb, and then spread to the spinal cord,
brainstem, substantia nigra and cerebral cortex. In the third article of this
special issue, Kelly Del Tredici and Heiko Braak review their and others’
findings (3), which are consistent with the spreading of pathology over time.
During the past eight years, much experimental evidence has been adduced to
support the prion-like spreading of α-synuclein aggregates. The first strong
indication came from PD patients who had received striatal grafts of embryonic
neural tissue to replace the function of lost nigral dopaminergic neurons. When
these patients died a decade or more after transplantation, some of the grafted
neurons had developed Lewy pathology. In the fourth contribution, Nolwen Rey,
Sonia George and Patrik Brundin summarise what is known about the prion-like
spreading of aggregated α-synuclein and discuss the methods used to detect
seeding and spreading of pathology (4).
In PD, the neuronal Lewy pathology appears to form first in nerve
terminals, where soluble α-synuclein is located. This may lead to synaptic
dysfunction and retrograde degeneration, with nerve cell loss being a later
event. In the fifth article, Arianna Bellucci, Nicola Mercuri, Annalena Venneri,
Gaia Faustini, Francesca Longhena, Marina Pizzi, Cristina Missale and PierFranco
Spano discuss what is known about the physiological function of α-synuclein and
its ordered assembly in relation to synaptic loss and connectome dysfunction
(5). A major objective behind the identification of novel disease mechanisms is
to discover new therapeutic targets. The final contribution by Elvira Valera,
Giacomo Compagnoni and Eliezer Masliah discusses novel strategies to treat
synucleinopathies, with an emphasis on MSA (6). Aggregation of α-synuclein and
chaperones that influence its aggregation are important targets, since the
ordered assembly of α-synuclein constitutes the gain of toxic function that
underlies synucleinopathies. The ordered assembly of proteins associated with
neurodegenerative diseases, be they Aβ, tau or α-synuclein, is
concentration-dependent. Reduced production and increased clearance of
α-synuclein are therefore valid targets for therapy. Besides its cell autonomous
effects, a reduction in cytosolic α-synuclein is also likely to reduce
intercellular propagation, which has emerged as an important contributor to
disease pathogenesis. Immunotherapy and degradation by extracellular proteases
may target the intercellular transfer of α-synuclein aggregates directly.
The process underlying sporadic synucleinopathies may originate in
localised portions of the nervous system. What predisposes certain brain regions
and cell types to the assembly of α-synuclein into oligomers and filaments is
unknown. Could somatic SNCA mutations play a role? Unlike dominantly inherited
forms of synucleinopathies, where half of the expressed α-synuclein molecules
are either mutant or over-expressed, most cells express normal levels of
wild-type protein in sporadic cases of disease. In these cases, the early events
may be followed by the more deterministic spreading of pathology, which will
eventually give rise to disease symptoms. The long preclinical phase of
synucleinopathies augurs well for the development of therapies.
Accepted Article This article is protected by copyright. All rights
reserved.
References
1 Barker R, Williams-Gray C. The spectrum of clinical features with
alpha-synuclein pathology. Neuropathol Appl Neurobiol 2016; 42: xx-xx.
2 Stefanova N, Wenning GK. Multiple system atrophy: emerging targets for
interventional therapies. Neuropathol Appl Neurobiol 2016; 42: xx-xx.
3 Del Tredici K, Braak H. Sporadic Parkinson’s disease: development and
distribution of α-synuclein pathology. Neuropathol Appl Neurobiol 2016: 42:
xx-xx.
4 Rey NL, George S, Brundin P. Spreading the word: precise animal models
and validated methods are vital when evaluating prion-like behaviour of
alpha-synuclein. Neuropathol Appl Neurobiol 2016: 42: xx-xx.
5 Bellucci A, Mercuri NB, Venneri A, Faustini G, Longhena F, Pizzi M,
Missale C, Spano P. Parkinson’s disease: from synaptic loss to connectome
dysfunction. Neuropathol Appl Neurobiol 2016; 42: xxxx.
6 Valera E, Compagnoni GM, Masliah E. Novel treatment strategies targeting
alpha-synuclein in multiple system atrophy as a model of synucleinopathy.
Neuropathol Appl Neurobiol 2016; 42: xx-xx.
Review: An update on clinical, genetic and pathological aspects of
frontotemporal lobar degenerations
Tammaryn Lashley1, Jonathan D. Rohrer2, Simon Mead3 andTamas Revesz1,*
Article first published online: 6 JUL 2015
DOI: 10.1111/nan.12250
© 2015 British Neuropathological Society
Keywords:classification;frontotemporal dementia;frontotemporal lobar
degeneration;FUS;pathology;tau;TDP-43
ABSTRACT
The development of our understanding of frontotemporal dementia (FTD) has
gathered pace over the last 10 years. After taking a back seat to Alzheimer's
disease for many years FTD has emerged as a significant group of heterogeneous
diseases often affecting people under the age of 65. FTD has also been brought
into the spotlight as the major disease entities of the group have clinical,
genetic and pathological links to motor neuron disease/amyotrophic lateral
sclerosis, indicating that they form a disease spectrum. In this review, we
overview how the pathological concept of frontotemporal lobar degeneration
(FTLD) and the clinical concept of FTD evolved and show that FTLD, once thought
of as a single disorder, represents a heterogeneous group of diseases with
overlapping clinical symptoms, multiple causative genes and varying underlying
pathology. We also provide a brief summary of the clinical manifestations,
summarize the major genetic aspects and describe the main pathological features
seen in the different subtypes of FTLD. We also summarize the correlations that
exist between clinical presentations and pathological variants. An overview of
the main pathogenic mechanisms is also provided.
SNIP...
Recent experimental data indicate that tau can show prion-like propagation
and spread, which is consistent with pathological disease progression in human
disease [74].
TDP-43 also has an N-terminal domain, two RNA-recognition motifs (RRMs)
involved in RNA and DNA binding and its glycine-rich C-terminal region contains
most of the mutations causing familial MND/ALS and rarely familial FTD
[108,109]. The C-terminal region of TDP-43 contains a prion-like protease
resistant domain [110].
There is now evidence to suggest that TDP-43 in inclusions, the majority of
which have been shown to show amyloid features [114], has cellular prion-like
properties, which could have relevance for the pathomechanism of FTLD-TDP [115].
The disease-associated TDP-43 making up the inclusions, is thought to exercise
its deleterious effect via toxic gain of function due to overexpression or
mutant forms, but given the number of its functions it is also likely that a
loss of function effect also has a role in the pathogenesis of FTLD-TDP.
FTLD-TDP has recently been reported to be associated with chronic traumatic
encephalopathy [116]. TDP43-positive inclusions are also found in around 90% of
patients with hippocampal sclerosis, which is also a feature in the majority of
FTLD-TDP suggesting a special relationship between these two pathologies
[117,118].
=========***************=========
***>>>In the third article of this special issue, Kelly Del
Tredici and Heiko Braak review their and others’ findings (3), which are
consistent with the spreading of pathology over time.
***During the past eight years, much experimental evidence has been adduced
to support the prion-like spreading of α-synuclein aggregates.
***The first strong indication came from PD patients who had received
striatal grafts of embryonic neural tissue to replace the function of lost
nigral dopaminergic neurons. When these patients died a decade or more after
transplantation, some of the grafted neurons had developed Lewy pathology. In
the fourth contribution, Nolwen Rey, Sonia George and Patrik Brundin summarise
what is known about the prion-like spreading of aggregated α-synuclein and
discuss the methods used to detect seeding and spreading of pathology
(4).<<<***
=========**************==========
WHAT IF, friendly fire, pass if forward, iatrogenic, plays a role with the
spreading with some of these Synucleinopathies, what if?...tss
Genetics (V Bonifati, Section Editor) Current Neurology and Neuroscience
Reports
November 2014, 14:495
First online: 14 September 2014
Prion-like Mechanisms in the Pathogenesis of Tauopathies and
Synucleinopathies Michel GoedertAffiliated withMRC Laboratory of Molecular
Biology Email author , Ben FalconAffiliated withMRC Laboratory of Molecular
Biology , Florence ClavagueraAffiliated withDepartment of Neuropathology,
Institute of Pathology , Markus TolnayAffiliated withDepartment of
Neuropathology, Institute of Pathology
$39.95 / €34.95 / £29.95 *
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Get Access Topical Collection Topical Collection on Genetics Abstract
Neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s
disease, are characterized by the abnormal aggregation of a small number of
intracellular proteins, with tau and α-synuclein being the most commonly
affected. Until recently, the events leading to aggregate formation were
believed to be entirely cell-autonomous, with protein misfolding occurring
independently in many cells. It is now believed that protein aggregates form in
a small number of brain cells, from which they propagate intercellularly through
templated recruitment, reminiscent of the mechanisms by which prions spread
through the nervous system.
Keywords Tau protein Alpha-synuclein Prions Neurodegeneration
Synucleinopathies: Past, Present and Future, iatrogenic, what if?
is Alzheimer’s a Transmissible Spongiform Encephalopathy TSE Prion disease
? that is the question...
I would kindly like to comment further on ;
Alzheimer-type brain pathology may be transmitted by grafts of dura mater
26/01/2016 By Karl Frontzek, et al.:
Original article | Published 26 January 2016,
doi:10.4414/smw.2016.14287
Cite this as: Swiss Med Wkly. 2016;146:w14287
Amyloid-β pathology and cerebral amyloid angiopathy are frequent in
iatrogenic Creutzfeldt-Jakob disease after dural grafting
MY comment as follows ;
Evidence for human transmission of amyloid-β pathology and cerebral amyloid
angiopathy
07 02:27 AM
Terry S. Singeltary Sr. said:
re-Evidence for human transmission of amyloid-β pathology and cerebral
amyloid angiopathy
2015-12-07 02:27 AM
Terry S. Singeltary Sr. said: re-Evidence for human transmission of
amyloid- βpathology and cerebral amyloid angiopathy Nature 525, 247?250 (10
September 2015) doi:10.1038/nature15369 Received 26 April 2015 Accepted 14
August 2015 Published online 09 September 2015 Updated online 11 September 2015
Erratum (October, 2015)
I would kindly like to comment on the Nature Paper, the Lancet reply, and
the newspaper articles.
First, I applaud Nature, the Scientist and Authors of the Nature paper, for
bringing this important finding to the attention of the public domain, and the
media for printing said findings.
Secondly, it seems once again, politics is getting in the way possibly of
more important Transmissible Spongiform Encephalopathy TSE Prion scientific
findings. findings that could have great implications for human health, and
great implications for the medical surgical arena. but apparently, the
government peer review process, of the peer review science, tries to intervene
again to water down said disturbing findings.
where have we all heard this before? it’s been well documented via the BSE
Inquiry. have they not learned a lesson from the last time?
we have seen this time and time again in England (and other Country’s) with
the BSE mad cow TSE Prion debacle.
That ‘anonymous' Lancet editorial was disgraceful. The editor, Dick Horton
is not a scientist.
The pituitary cadavers were very likely elderly and among them some were on
their way to CJD or Alzheimer's. Not a bit unusual. Then the recipients ? who
got pooled extracts injected from thousands of cadavers ? were 100% certain to
have been injected with both seeds. No surprise that they got both diseases
going after thirty year incubations.
That the UK has a "system in place to assist science journalists" to squash
embargoed science reports they find ? alarming? is pathetic.
Sounds like the journalists had it right in the first place: ‘Alzheimer,s
may be a transmissible infection? in The Independent to ? You can catch
Alzheimer’s? in The Daily Mirror or ? Alzheimer’s bombshell" in The Daily
Express
if not for the journalist, the layperson would not know about these
important findings.
where would we be today with sound science, from where we were 30 years
ago, if not for the cloak of secrecy and save the industry at all cost
mentality?
when you have a peer review system for science, from which a government
constantly circumvents, then you have a problem with science, and humans die.
to date, as far as documented body bag count, with all TSE prion named to
date, that count is still relatively low (one was too many in my case, Mom
hvCJD), however that changes drastically once the TSE Prion link is made with
Alzheimer?s, the price of poker goes up drastically.
so, who makes that final decision, and how many more decades do we have to
wait?
the iatrogenic mode of transmission of TSE prion, the many routes there
from, load factor, threshold from said load factor to sub-clinical disease, to
clinical disease, to death, much time is there to spread a TSE Prion to
anywhere, but whom, by whom, and when, do we make that final decision to do
something about it globally? how many documented body bags does it take? how
many more decades do we wait? how many names can we make up for one disease, TSE
prion?
Professor Collinge et al, and others, have had troubles in the past with
the Government meddling in scientific findings, that might in some way involve
industry, never mind human and or animal health.
FOR any government to continue to circumvent science for monetary gain,
fear factor, or any reason, shame, shame on you.
in my opinion, it?s one of the reasons we are at where we are at to date,
with regards to the TSE Prion disease science i.e. money, industry, politics,
then comes science, in that order.
greed, corporate, lobbyist there from, and government, must be removed from
the peer review process of sound science, it?s bad enough having them in the
pharmaceutical aspect of healthcare policy making, in my opinion.
my mother died from confirmed hvCJD, and her brother (my uncle) Alzheimer?s
of some type (no autopsy?). just made a promise, never forget, and never let
them forget, before I do.
I kindly wish to remind the public of the past, and a possible future we
all hopes never happens again. ...
[9. Whilst this matter is not at the moment directly concerned with the
iatrogenic CJD cases from hgH, there remains a possibility of litigation here,
and this presents an added complication. There are also results to be made
available shortly (1) concerning a farmer with CJD who had BSE animals, (2) on
the possible transmissibility of Alzheimer?s and (3) a CMO letter on prevention
of iatrogenic CJD transmission in neurosurgery, all of which will serve to
increase media interest.]
Terry S. Singeltary Sr. Bacliff, Texas USA 77518
snip...see Singeltary comment ;
Subject: 1992 IN CONFIDENCE TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO
PRIMATES POSSIBILITY ON A TRANSMISSIBLE PRION REMAINS OPEN
BSE101/1 0136
IN CONFIDENCE
CMO
From: . Dr J S Metiers 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
recognised 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 emphasises 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.
1
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.
J S METTERS Room 509 Richmond House Pager No: 081-884 3344 Callsign: DOH
832 llllYc!eS 2 92/11.4/1.2
>>> The only tenable public line will be that "more research is
required’’ <<<
>>> possibility on a transmissible prion remains
open<<<
O.K., so it’s about 23 years later, so somebody please tell me, when is
"more research is required’’ enough time for evaluation ?
Self-Propagative Replication of Ab Oligomers Suggests Potential
Transmissibility in Alzheimer Disease
*** Singeltary comment PLoS ***
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion
disease, Iatrogenic, what if ?
Posted by flounder on 05 Nov 2014 at 21:27 GMT
Sunday, November 22, 2015
*** Effect of heating on the stability of amyloid A (AA) fibrils and the
intra- and cross-species transmission of AA amyloidosis Abstract
Amyloid A (AA) amyloidosis is a protein misfolding disease characterized by
extracellular deposition of AA fibrils. AA fibrils are found in several tissues
from food animals with AA amyloidosis. For hygienic purposes, heating is widely
used to inactivate microbes in food, but it is uncertain whether heating is
sufficient to inactivate AA fibrils and prevent intra- or cross-species
transmission. We examined the effect of heating (at 60 °C or 100 °C) and
autoclaving (at 121 °C or 135 °C) on murine and bovine AA fibrils using Western
blot analysis, transmission electron microscopy (TEM), and mouse model
transmission experiments. TEM revealed that a mixture of AA fibrils and
amorphous aggregates appeared after heating at 100 °C, whereas autoclaving at
135 °C produced large amorphous aggregates. AA fibrils retained antigen
specificity in Western blot analysis when heated at 100 °C or autoclaved at 121
°C, but not when autoclaved at 135 °C. Transmissible pathogenicity of murine and
bovine AA fibrils subjected to heating (at 60 °C or 100 °C) was significantly
stimulated and resulted in amyloid deposition in mice. Autoclaving of murine AA
fibrils at 121 °C or 135 °C significantly decreased amyloid deposition.
Moreover, amyloid deposition in mice injected with murine AA fibrils was more
severe than that in mice injected with bovine AA fibrils. Bovine AA fibrils
autoclaved at 121 °C or 135 °C did not induce amyloid deposition in mice. These
results suggest that AA fibrils are relatively heat stable and that similar to
prions, autoclaving at 135 °C is required to destroy the pathogenicity of AA
fibrils. These findings may contribute to the prevention of AA fibril
transmission through food materials to different animals and especially to
humans.
Purchase options Price * Issue Purchase USD 511.00 Article Purchase USD
54.00
Transmission of Creutzfeldt-Jakob disease to a chimpanzee by electrodes
contaminated during neurosurgery.
Gibbs CJ Jr, Asher DM, Kobrine A, Amyx HL, Sulima MP, Gajdusek DC.
Laboratory of Central Nervous System Studies, National Institute of Neurological
Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
Stereotactic multicontact electrodes used to probe the cerebral cortex of a
middle aged woman with progressive dementia were previously implicated in the
accidental transmission of Creutzfeldt-Jakob disease (CJD) to two younger
patients. The diagnoses of CJD have been confirmed for all three cases. More
than two years after their last use in humans, after three cleanings and
repeated sterilisation in ethanol and formaldehyde vapour, the electrodes were
implanted in the cortex of a chimpanzee. Eighteen months later the animal became
ill with CJD. This finding serves to re-emphasise the potential danger posed by
reuse of instruments contaminated with the agents of spongiform
encephalopathies, even after scrupulous attempts to clean them.
Friday, January 10, 2014
vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type
prion disease, what it ???
Greetings Friends, Neighbors, and Colleagues,
Thursday, January 14, 2016
Preventable Tragedies: Superbugs and How Ineffective Monitoring of Medical
Device Safety Fails Patients REPORT
how can it be, HOW CAN IT BE $$$ not a word about CJD GSS FFI VPSPR TSE
Prions that I saw...absolutely crazy, WE ARE MISSING THE BIGGER PICTURE!
how many victims that will never be reported ???
Sunday, January 17, 2016
Of Grave Concern Heidenhain Variant Creutzfeldt Jakob Disease
Tuesday, January 26, 2016
Amyloid-β pathology and cerebral amyloid angiopathy are frequent in
iatrogenic Creutzfeldt-Jakob disease after dural grafting
Tuesday, January 26, 2016
Alzheimer-type brain pathology may be transmitted by grafts of dura mater
Suspect symptoms
What if you can catch old-fashioned CJD by eating meat from a sheep
infected with scrapie?
28 Mar 01
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...
Research Project: TRANSMISSION, DIFFERENTIATION, AND PATHOBIOLOGY OF
TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES
Title: Transmission of scrapie prions to primate after an extended silent
incubation period
Authors
item Comoy, Emmanuel - item Mikol, Jacqueline - item Luccantoni-Freire,
Sophie - item Correia, Evelyne - item Lescoutra-Etchegaray, Nathalie - item
Durand, Valérie - item Dehen, Capucine - item Andreoletti, Olivier - item
Casalone, Cristina - item Richt, Juergen item Greenlee, Justin item Baron,
Thierry - item Benestad, Sylvie - item Hills, Bob - item Brown, Paul - item
Deslys, Jean-Philippe -
Submitted to: Scientific Reports Publication Type: Peer Reviewed Journal
Publication Acceptance Date: May 28, 2015 Publication Date: June 30, 2015
Citation: Comoy, E.E., Mikol, J., Luccantoni-Freire, S., Correia, E.,
Lescoutra-Etchegaray, N., Durand, V., Dehen, C., Andreoletti, O., Casalone, C.,
Richt, J.A., Greenlee, J.J., Baron, T., Benestad, S., Brown, P., Deslys, J.
2015. Transmission of scrapie prions to primate after an extended silent
incubation period. Scientific Reports. 5:11573.
Interpretive Summary: The transmissible spongiform encephalopathies (also
called prion diseases) are fatal neurodegenerative diseases that affect animals
and humans. The agent of prion diseases is a misfolded form of the prion protein
that is resistant to breakdown by the host cells. Since all mammals express
prion protein on the surface of various cells such as neurons, all mammals are,
in theory, capable of replicating prion diseases. One example of a prion
disease, bovine spongiform encephalopathy (BSE; also called mad cow disease),
has been shown to infect cattle, sheep, exotic undulates, cats, non-human
primates, and humans when the new host is exposed to feeds or foods contaminated
with the disease agent. The purpose of this study was to test whether non-human
primates (cynomologous macaque) are susceptible to the agent of sheep scrapie.
After an incubation period of approximately 10 years a macaque developed
progressive clinical signs suggestive of neurologic disease. Upon postmortem
examination and microscopic examination of tissues, there was a widespread
distribution of lesions consistent with a transmissible spongiform
encephalopathy. This information will have a scientific impact since it is the
first study that demonstrates the transmission of scrapie to a non-human primate
with a close genetic relationship to humans. This information is especially
useful to regulatory officials and those involved with risk assessment of the
potential transmission of animal prion diseases to humans. Technical Abstract:
Classical bovine spongiform encephalopathy (c-BSE) is an animal prion disease
that also causes variant Creutzfeldt-Jakob disease in humans. Over the past
decades, c-BSE's zoonotic potential has been the driving force in establishing
extensive protective measures for animal and human health.
*** In complement to the recent demonstration that humanized mice are
susceptible to scrapie, we report here the first observation of direct
transmission of a natural classical scrapie isolate to a macaque after a 10-year
incubation period. Neuropathologic examination revealed all of the features of a
prion disease: spongiform change, neuronal loss, and accumulation of PrPres
throughout the CNS.
*** This observation strengthens the questioning of the harmlessness of
scrapie to humans, at a time when protective measures for human and animal
health are being dismantled and reduced as c-BSE is considered controlled and
being eradicated.
*** Our results underscore the importance of precautionary and protective
measures and the necessity for long-term experimental transmission studies to
assess the zoonotic potential of other animal prion strains.
COMMENT SUBMISSION TERRY S. SINGELTARY SR.
WITH regards to Docket No. APHIS-2007-0127 Scrapie in Sheep and Goats, I
kindly submit the following ;
>>>The last major revision of the scrapie regulations occurred on
August 21, 2001, when we published in theFederal Register(66 FR 43964, Docket
No. 97-093-5) a final rule amending part 79 by imposing additional restrictions
on the interstate movement of sheep and goats.<<<
Indeed, much science has changed about the Scrapie TSE prion, including
more science linking Scrapie to humans. sadly, politics, industry, and trade,
have not changed, and those usually trump sound science, as is the case with all
Transmissible Spongiform Encephalopathy TSE Prion disease in livestock producing
animals and the OIE. we can look no further at the legal trading of the Scrapie
TSE prion both typical and atypical of all strains, and CWD all stains. With as
much science of old, and now more new science to back this up, Scrapie of all
types i.e. atypical and typical, BSE all strains, and CWD all strains, should be
regulated in trade as BSE TSE PRION. In fact, I urge APHIS et al and the OIE,
and all trading partners to take heed to the latest science on the TSE prion
disease, all of them, and seriously reconsider the blatant disregards for human
and animal health, all in the name of trade, with the continued relaxing of TSE
Prion trade regulations through the ‘NEGLIGIBLE BSE RISK’ PROGRAM, which was set
up to fail in the first place. If the world does not go back to the ‘BSE RISK
ASSESSMENTS’, enhance, and or change that assessment process to include all TSE
prion disease, i.e. ‘TSE RISK ASSESSMENT’, if we do not do this and if we
continue this farce with OIE and the USDA et al, and the ‘NEGLIGIBLE BSE RISK’
PROGRAM, we will never eradicate the TSE prion aka mad cow type disease, they
will continue to mutate and spread among species of human and animal origin, and
they will continue to kill. ...
please see ;
O.05: Transmission of prions to primates after extended silent incubation
periods: Implications for BSE and scrapie risk assessment in human populations
Emmanuel Comoy, Jacqueline Mikol, Valerie Durand, Sophie Luccantoni,
Evelyne Correia, Nathalie Lescoutra, Capucine Dehen, and Jean-Philippe Deslys
Atomic Energy Commission; Fontenay-aux-Roses, France
Prion diseases (PD) are the unique neurodegenerative proteinopathies
reputed to be transmissible under field conditions since decades. The
transmission of Bovine Spongiform Encephalopathy (BSE) to humans evidenced that
an animal PD might be zoonotic under appropriate conditions. Contrarily, in the
absence of obvious (epidemiological or experimental) elements supporting a
transmission or genetic predispositions, PD, like the other proteinopathies, are
reputed to occur spontaneously (atpical animal prion strains, sporadic CJD
summing 80% of human prion cases). Non-human primate models provided the first
evidences supporting the transmissibiity of human prion strains and the zoonotic
potential of BSE. Among them, cynomolgus macaques brought major information for
BSE risk assessment for human health (Chen, 2014), according to their
phylogenetic proximity to humans and extended lifetime. We used this model to
assess the zoonotic potential of other animal PD from bovine, ovine and cervid
origins even after very long silent incubation periods.
*** We recently observed the direct transmission of a natural classical
scrapie isolate to macaque after a 10-year silent incubation period,
***with features similar to some reported for human cases of sporadic CJD,
albeit requiring fourfold long incubation than BSE. Scrapie, as recently evoked
in humanized mice (Cassard, 2014),
***is the third potentially zoonotic PD (with BSE and L-type BSE),
***thus questioning the origin of human sporadic cases. We will present an
updated panorama of our different transmission studies and discuss the
implications of such extended incubation periods on risk assessment of animal PD
for human health.
===============
***thus questioning the origin of human sporadic cases***
===============
snip...see ;
Monday, November 16, 2015
*** Docket No. APHIS-2007-0127 Scrapie in Sheep and Goats Terry Singeltary
Sr. Submission ***
Thursday, January 14, 2016
EMERGING ANIMAL DISEASES Actions Needed to Better Position USDA to Address
Future Risks Report to the Chairman, Committee on Energy and Commerce, House of
Representatives December 2015 GAO-16-132
GAO
Tuesday, January 26, 2016
USDA National Program 103 ANIMAL HEALTH TSE PRION ACCOMPLISHMENT REPORT
2011-2015 March 2015
*** Needless conflict ***
Nature 485, 279–280 (17 May 2012) doi:10.1038/485279b
Published online 16 May 2012
Terry S. Singeltary Sr. said:
I kindly wish to submit the following please ;
Comments on technical aspects of the risk assessment were then submitted to
FSIS.
Comments were received from Food and Water Watch, Food Animal Concerns
Trust (FACT), Farm Sanctuary, R-CALF USA, Linda A Detwiler, and Terry S.
Singeltary.
This document provides itemized replies to the public comments received on
the 2005 updated Harvard BSE risk assessment. Please bear the following points
in mind:
Owens, Julie
From: Terry S. Singeltary Sr. [flounder9@verizon.net]
Sent: Monday, July 24, 2006 1:09 PM
To: FSIS RegulationsComments
Subject: [Docket No. FSIS-2006-0011] FSIS Harvard Risk Assessment of Bovine
Spongiform Encephalopathy (BSE)
Page 1 of 98
FSIS, USDA, REPLY TO SINGELTARY
Singeltary to APHIS FDA USDA et al ;
Thursday, October 22, 2015
Former Ag Secretary Ann Veneman talks women in agriculture and we talk mad
cow disease USDA and what really happened
Scrapie has been known since 1732...tss
2.2 History
Scrapie is not only the prototype of TSEs but also the prion disease with
the longest history of publication. The fi rst authentic report on scrapie was
written in Germany and dates back to year 1750 (Leopoldt 1750 ) . However, a
later publication (Comber 1772 ) even mentions cases in England that occurred
already in 1732. Several authors at later times even referred to much earlier
time periods, spanning from Roman times up to the seventeenth century, but
without giving corresponding references (for a detailed review see Schneider et
al. 2008 ) . Moreover in former times, many sheep diseases were confused with
scrapie. Other dif fi culties were the various names that were used to describe
this disease throughout Europe: “Goggles”, “Ricketts”, “Rubbing Disease” and
“Trotting Disease” in England, “Scratchie” and “Yeukie pine” in Scotland,
“Basqvilla Disease” in Spain, “La maladie convulsive”, “La Tremblante” and
“Prurigo lumbaire” in France, “Rida” in Iceland, “Gnave-og travesjuke” in Norway
and “Gnubberkrankheit”, “Petermännchen”, “Traber” or “Reiberkrankheit” in
Germany. Altogether, at least 42 different names were used in Europe and India
(Schneider et al. 2008 ) for this disease in small ruminants.
The infectious nature of scrapie was already reckoned in the eighteenth
century (Leopoldt 1750 ). In the following decades and centuries, different
transmission routes were discussed in which the sexual intercourse was the most
suspected modus. However, among other causes like atmospheric disturbances, a
few authors proposed a mere coexistence of infected and non-infected animals or
a spontaneous origin of the diseases (Schneider et al. 2008 ) . In addition, a
broad consent existed already in the nineteenth century concerning the role of
hereditary factors for scrapie. Initially, a hereditary predisposition and the
transmission by asymptomatic animals were assumed (Thaer 1821 ; von Richthofen
1821 ) and even the existence of hereditary and non-hereditary scrapie forms was
postulated (von Richthofen 1826 ) .
>>>Close to 200 years ago, James Parkinson published his 1817
monograph entitled “An Essay on the Shaking Palsy”, in which he reported the
first detailed clinical description of the disease that Jean- Martin Charcot
named after him in 1872.<<<
*** An Essay on the Shaking Palsy
Alzheimer’s disease is named after Dr. Alois Alzheimer. In 1906, Dr.
Alzheimer noticed changes in the brain tissue of a woman who had died of an
unusual mental illness. Her symptoms included memory loss, language problems,
and unpredictable behavior. After she died, he examined her brain and found many
abnormal clumps (now called amyloid plaques) and tangled bundles of fibers (now
called neurofibrillary, or tau, tangles).
Creutzfeldt-Jakob disease was first described by Creutzfeldt in 1920 and by
Jakob in 1921. It was set apart as a new entity on the basis of its distinctive
pathological features. Based on 8 cases, Jakob (1923) gave a lucid outline of
the major clinical features.
Terry S. Singeltary Sr. Bacliff, Texas
