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From: TSS ()
Subject: Strain-specified characteristics of mouse synthetic prions
Date: February 8, 2005 at 12:42 pm PST

-------- Original Message --------
Subject: Strain-specified characteristics of mouse synthetic prions
Date: Tue, 8 Feb 2005 12:58:36 -0600
From: "Terry S. Singeltary Sr."
Reply-To: Bovine Spongiform Encephalopathy
To: BSE-L@LISTSERV.KALIV.UNI-KARLSRUHE.DE


##################### Bovine Spongiform Encephalopathy #####################

Published online before print January 25, 2005, 10.1073/pnas.0409079102
PNAS | February 8, 2005 | vol. 102 | no. 6 | 2168-2173

NEUROSCIENCE
Strain-specified characteristics of mouse synthetic prions

Giuseppe Legname *, {dagger} {ddagger} , Hoang-Oanh B. Nguyen *, Ilia
V. Baskakov * § , Fred E. Cohen *, ¶, ||, Stephen J.
DeArmond * {ddagger} , ** and Stanley B. Prusiner *, {dagger} {ddagger}
, ||, {dagger} {dagger}

*Institute for Neurodegenerative Diseases and Departments of {dagger}
Neurology, ¶Cellular and Molecular Pharmacology, ||Biochemistry and
Biophysics, and **Pathology, University of California, San Francisco, CA
94143

Contributed by Stanley B. Prusiner, December 6, 2004

Synthetic prions were produced in our laboratory by using recombinant
mouse prion protein (MoPrP) composed of residues 89-230. The first mouse
synthetic prion strain (MoSP1) was inoculated into transgenic (Tg) 9949
mice expressing N-terminally truncated MoPrP({Delta} 23-88) and WT FVB
mice expressing full-length MoPrP. On first and second passage in Tg9949
mice, MoSP1 prions caused disease in 516 ± 27 and 258 ± 25 days,
respectively; numerous, large vacuoles were found in the brainstem and
gray matter of the cerebellum. MoSP1 prions passaged in Tg9949 mice were
inoculated into FVB mice; on first and second passage, the FVB mice
exhibited incubation times of 154 ± 4 and 130 ± 3 days, respectively. In
FVB mice, vacuolation was less intense but more widely distributed, with
numerous lesions in the hippocampus and cerebellar white matter. This
constellation of widespread neuropatho-logic changes was similar to that
found in FVB mice inoculated with Rocky Mountain Laboratory (RML)
prions, a strain derived from a sheep with scrapie. Conformational
stability studies showed that the half-maximal GdnHCl (Gdn1/2)
concentration for denaturation of MoSP1 prions passaged in Tg9949 mice
was {approx} 4.2 M; passage in FVB mice reduced the Gdn1/2 value to
{approx} 1.7 M. RML prions passaged in either Tg9949 or FVB mice
exhibited Gdn1/2 values of {approx} 1.8 M. The incubation times,
neuropathological lesion profiles, and Gdn1/2 values indicate that MoSP1
prions differ from RML and many other prion strains derived from sheep
with scrapie and cattle with bovine spongiform encephalopathy.

neurodegeneration

------------------------------------------------------------------------
Author contributions: G.L., I.V.B., F.E.C., and S.B.P. designed
research; H.-O.B.N. and S.J.D. performed research; G.L., S.J.D., and
S.B.P. analyzed data; S.B.P. contributed new reagents/analytic tools;
and G.L., S.J.D., and S.B.P. wrote the paper.

Abbreviations: PrP, prion protein; MoPrP, mouse PrP; PrPSc,
disease-causing isoform of PrP; MoSP1, mouse synthetic prion1; rec,
recombinant; Tg, transgenic; RML, Rocky Mountain Laboratory; Gdn1/2,
half-maximal GdnHCl; HuM, human-mouse; PK, proteinase K.

{ddagger} G.L., S.J.D., and S.B.P. have a financial interest in InPro
Biotechnology, Inc.

§ Present address: Medical Biotechnology Center, University of Maryland
Biotechnology Institute, Baltimore, MD 21201.

{dagger} {dagger} To whom correspondence should be addressed. E-mail:
stanley@ind.ucsf.edu .

© 2005 by The National Academy of Sciences
of the USA


http://www.pnas.org/cgi/content/abstract/102/6/2168?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=prion&searchid=1107887303603_6112&stored_search=&FIRSTINDEX=0&volume=102&issue=6&journalcode=pnas


Greetings list members,


> The incubation times, neuropathological lesion profiles, and Gdn1/2
> values indicate that MoSP1 prions differ from RML and many other prion
> strains derived from sheep with scrapie and cattle with bovine
> spongiform encephalopathy.


THIS is what i was most curious about when everyone (well not everybody)
jumped on the ''spontaneous sCJD/TSE bandwagon again''. i wanted to know
if the synthetic TSE (which stan produced) was infectious. HERE we
find it is, BUT, it does not seem to match other TSEs. SO the myth
or theory that 85%+ of all sporadic CJD (or CJDs) just happen
spontaneously (without any route or source of agent) from a misfolding
prion
is pretty much put to rest. i never believed it anyway. there was never
any science
to back it up.


> SPONTANEOUS PRION DISEASES
> The discovery that a small change in the condition of a cell can cause
> the development of a prion offers an explanation, says Prusiner, for
> the sporadic form of Creutzfeldt Jakob disease (CJD), which is
> responsible for 85 percent of cases of prion disease in humans
> (occurring in 1 or 2 people per million) and is believed to develop
> spontaneously. It also supports his belief, he says, that sporadic
> forms of prion disease are caused by prion strains that are different
> from the one causing bovine spongiform encephalopathy (BSE) in cattle
> in Britain. He says he thinks that sporadic BSE will be found in one
> to five cattle per million and predicts such numbers will be found
> with increased testing for BSE.


http://www.mnbeef.org/BSE/prion_finding_offers_insight_int.htm


THIS was total BSeee and everybody knew it...

OH, and by the way, see the increase in sporadic CJD over the
last decade or so here (excluding N. America).

http://www.eurocjd.ed.ac.uk/sporadic.htm

BSE prions propagate as either variant CJD-like or sporadic CJD-like
prion strains in transgenic mice expressing human prion protein

Emmanuel A. Asante, Jacqueline M. Linehan, Melanie Desbruslais, Susan
Joiner, Ian Gowland, Andrew L. Wood, Julie Welch, Andrew F. Hill, Sarah
E. Lloyd, Jonathan D.F. Wadsworth and John Collinge1

MRC Prion Unit and Department of Neurodegenerative Disease, Institute of
Neurology, University College, Queen Square, London WC1N 3BG, UK 1
Corresponding author e-mail: j.collinge@prion.ucl.ac.uk


Received August 1, 2002; revised September 24, 2002; accepted October
17, 2002

Abstract


Variant CreutzfeldtJakob disease (vCJD) has been recognized to date
only in individuals homozygous for methionine at PRNP codon 129. Here we
show that transgenic mice expressing human PrP methionine 129,
inoculated with either bovine spongiform encephalopathy (BSE) or variant
CJD prions, may develop the neuropathological and molecular phenotype of
vCJD, consistent with these diseases being caused by the same prion
strain. Surprisingly, however, BSE transmission to these transgenic
mice, in addition to producing a vCJD-like phenotype, can also result in
a distinct molecular phenotype that is indistinguishable from that of
sporadic CJD with PrPSc type 2. These data suggest that more than one
BSE-derived prion strain might infect humans; it is therefore possible
that some patients with a phenotype consistent with sporadic CJD may
have a disease arising from BSE exposure...

http://embojournal.npgjournals.com/cgi/content/full/21/23/6358

THE new findings of BASE in cattle in Italy of Identification of a
second bovine amyloidotic spongiform encephalopathy: Molecular
similarities with sporadic Creutzfeldt-Jakob disease


http://www.pnas.org/cgi/content/abstract/0305777101v1


Adaptation of the bovine spongiform encephalopathy agent to primates
and comparison with Creutzfeldt- Jakob disease: Implications for
human health

THE findings from Corinne Ida Lasmézas*, [dagger] , Jean-Guy Fournier*,
Virginie Nouvel*,

Hermann Boe*, Domíníque Marcé*, François Lamoury*, Nicolas Kopp [Dagger

] , Jean-Jacques Hauw§, James Ironside¶, Moira Bruce [||] , Dominique

Dormont*, and Jean-Philippe Deslys* et al, that The agent responsible
for French iatrogenic growth hormone-linked CJD taken as a control is
very different from vCJD but is similar to that found in one case of
sporadic CJD and one sheep scrapie isolate;

http://www.pnas.org/cgi/content/full/041490898v1

Characterization of two distinct prion strains
derived from bovine spongiform encephalopathy
transmissions to inbred mice

Sarah E. Lloyd, Jacqueline M. Linehan, Melanie Desbruslais,
Susan Joiner, Jennifer Buckell, Sebastian Brandner,
Jonathan D. F. Wadsworth and John Collinge

Correspondence
John Collinge
j.collinge@prion.ucl.ac.uk

MRC Prion Unit and Department of Neurodegenerative Disease, Institute of
Neurology,
University College, London WC1N 3BG, UK
Received 9 December 2003
Accepted 27 April 2004

Distinct prion strains can be distinguished by differences in incubation
period, neuropathology
and biochemical properties of disease-associated prion protein (PrPSc)
in inoculated mice.
Reliable comparisons of mouse prion strain properties can only be
achieved after passage in
genetically identical mice, as host prion protein sequence and genetic
background are known
to modulate prion disease phenotypes. While multiple prion strains have
been identified in
sheep scrapie and CreutzfeldtJakob disease, bovine spongiform
encephalopathy (BSE) is
thought to be caused by a single prion strain. Primary passage of BSE
prions to different lines
of inbred mice resulted in the propagation of two distinct PrPSc types,
suggesting that two
prion strains may have been isolated. To investigate this further, these
isolates were
subpassaged in a single line of inbred mice (SJL) and it was confirmed
that two distinct prion
strains had been identified. MRC1 was characterized by a short
incubation time (110±3 days),
a mono-glycosylated-dominant PrPSc type and a generalized diffuse
pattern of PrP-immunoreactive
deposits, while MRC2 displayed a much longer incubation time (155±1 days),
a di-glycosylated-dominant PrPSc type and a distinct pattern of
PrP-immunoreactive deposits
and neuronal loss. These data indicate a crucial involvement of the host
genome in modulating
prion strain selection and propagation in mice. It is possible that
multiple disease phenotypes
may also be possible in BSE prion infection in humans and other animals.

http://vir.sgmjournals.org/cgi/content/abstract/85/8/2471


REPORTS

Human Prion Protein with
Valine 129 Prevents Expression
of Variant CJD Phenotype

Jonathan D. F. Wadsworth, Emmanuel A. Asante,
Melanie Desbruslais, Jacqueline M. Linehan, Susan Joiner,
Ian Gowland, Julie Welch, Lisa Stone, Sarah E. Lloyd,
Andrew F. Hill,* Sebastian Brandner, John Collinge

Variant Creutzfeldt-Jakob disease (vCJD) is a unique and highly distinctive
clinicopathological and molecular phenotype of human prion disease
associated with infection with bovine spongiform encephalopathy (BSE)-like
prions. Here, we found that generation of this phenotype in transgenic mice
required expression of human prion protein (PrP) with methionine 129.
Expression of human PrP with valine 129 resulted in a distinct phenotype
and,
remarkably, persistence of a barrier to transmission of BSE-derived
prions on
subpassage. Polymorphic residue 129 of human PrP dictated propagation of
distinct prion strains after BSE prion infection. Thus, primary and
secondary
human infection with BSE-derived prions may result in sporadic CJD-like or
novel phenotypes in addition to vCJD, depending on the genotype of the
prion
source and the recipient.

snip...

In conclusion, we have demonstrated
that BSE and vCJD prion infection in
transgenic mice can result in the propaga-
tion of distinct molecular and neuropatho-
logical phenotypes dependent on host PrP
residue 129 and possibly other, as yet
unidentified, disease modifying loci (10).
These data predict a critical role for PRNP
codon 129 in governing the thermodynamic
permissibility of human PrPSc conformation
that can be interpreted within a conforma-
tional selection model of prion transmission
barriers (17-19) (SOM text) and suggest
that there is no overlapping preferred
conformation for Val129 and Met129 human
PrP that can be generated as a result of
exposure to the vCJD/BSE prion strain.
Biophysical measurements suggest that this
powerful effect of residue 129 on prion
strain selection is likely to be mediated by
means of its effect on the conformation of
PrPSc or its precursors or on the kinetics of
their formation, as it has no measurable
effect on the folding, dynamics, or stability
of the normal cellular prion protein PrPC
(20).

Although caution must be exercised in
extrapolating from animal models, even
where, as here, faithful recapitulation of
molecular and pathological phenotypes is
possible, our findings argue that primary
human BSE prion infection, as well as sec-
ondary infection with vCJD prions by iatro-
genic routes, may not be restricted to a single
disease phenotype. These data, together with
the recent recognition of probable iatrogenic
transmission of vCJD prions to recipients of
blood {21, 22), including a PRNP codon 129
Met/Val heterozygous individual (22), re-
iterate the need to stratify all human prion
disease patients by PrPSc type. This surveil-
lance will facilitate rapid recognition of novel
PrPSc types and of any change in relative
frequencies of particular PrPSc subtypes in
relation to either BSE exposure patterns or
iatrogenic sources of vCJD prions.

References and Notes

snip...end

To whom correspondence should be addressed.
E-mail: j.collinge@prion.ucl.ac.uk

www.sciencemag.org SCIENCE VOL 306 3 DECEMBER 2004


Chronic Lymphocytic Inflammation Specifies the Organ Tropism of Prions

Mathias Heikenwalder,1* Nicolas Zeller,1* Harald Seeger,1* Marco
Prinz,1* Peter-Christian Klöhn,2 Petra
Schwarz,1 Nancy H. Ruddle,3 Charles Weissmann,2 Adriano Aguzzi1!

1Institute of Neuropathology, University Hospital of ZĂĽrich, CH-8091
ZĂĽrich, Switzerland. 2Medical Research Council Prion
Unit, Department of Neurodegenerative Diseases, Institute of Neurology,
Queen Square, London WC1N 3BG, UK. 3Department
of Epidemiology and Public Health and Section of Immunobiology, Yale
University School of Medicine, New Haven, CT
06520, USA.

*These authors contributed equally to this work.
Present address: Institute of Neuropathology, Georg-August-Universität,
D-37073 Göttingen, Germany.
!To whom correspondence should be addressed. E-mail:
adriano@pathol.unizh.ch

Prions typically accumulate in nervous and lymphoid
tissues. Because proinflammatory cytokines and immune
cells are required for lymphoid prion replication, we
tested whether inflammatory conditions affect prion
pathogenesis. We administered prions to mice with five
inflammatory diseases of kidney, pancreas or liver. In all
cases, chronic lymphocytic inflammation enabled prion
accumulation in otherwise prion-free organs.
Inflammatory foci consistently correlated with
lymphotoxin upregulation and ectopic induction of PrPCexpressing
FDC-M1+ cells, whereas inflamed organs of
mice lacking lymphotoxin-? or its receptor did not
accumulate PrPSc nor infectivity upon prion inoculation.
By expanding the tissue distribution of prions, chronic
inflammatory conditions may act as modifiers of natural
and iatrogenic prion transmission.

snip...

The above results indicate that chronic follicular
inflammation, induced by a variety of causes, specifies prion
tropism for otherwise prion-free organs. In most instances
infectivity tended to rise with time, suggesting local prion
replication. Organ-specific expression of one single proinflammatory
cytokine (LT?) or chemokine (SLC) sufficed to
establish unexpected prion reservoirs, suggesting
differentiation of ubiquitous stromal constituents into prionreplication
competent cells. In several instances, prion
concentration in individual inflamed organs approached that
of spleen long before any clinical manifestation of scrapie.
Inflamed non-lymphoid organs not only accumulated PrPSc,
but transmitted bona fide prion disease when inoculated into
healthy recipient mice.

Knowledge of the distribution of prions within infected
hosts is fundamental to consumer protection and prevention
of iatrogenic accidents. Based on the failure to transmit BSE
infectivity from any tissue but central nervous system,
intestinal, and lymphoid tissue (35), the risk to humans of
contracting prion infection from other organs has been
deemed small even in countries with endemic BSE. It may be
important now to test whether superimposed viral, microbial
or autoimmune pathologies of farm animals trigger
unexpected shifts in the organ tropism of prions. Conversely,
the lack of infectivity in burned out postinflammatory
pancreases suggests that anti-inflammatory regimens may
abolish ectopic prion reservoirs.

References and Notes ............snip...........end

/ www.sciencexpress.org / 20 January 2005 / Page 5 /
10.1126/science.1106460TSS


kind regards,
terry


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