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From: TSS ()
Subject: Beyond PrPres Type 1/Type 2 Dichotomy in Creutzfeldt-Jakob Disease
Date: March 18, 2008 at 11:55 am PST

Beyond PrPres Type 1/Type 2 Dichotomy in Creutzfeldt-Jakob Disease

Emmanuelle Uro-Coste1#, Hervé Cassard2#, Stéphanie Simon3, Séverine Lugan2,
Jean-Marc Bilheude4, Armand Perret-Liaudet5, James W. Ironside6, Stéphane
Haik7,8, Christelle Basset-Leobon1, Caroline Lacroux2, Katell Peoch'9,
Nathalie Streichenberger5, Jan Langeveld10, Mark W. Head6, Jacques Grassi3,
Jean-Jacques Hauw8, Francois Schelcher2, Marie Bernadette Delisle1, Olivier
Andréoletti2*

1 INSERM U858, Institut de Médecine Moléculaire de Rangueil and Service
d'Anatomie Pathologique et Histologie-Cytologie, C.H.U. Rangueil, Toulouse,
France2 UMR Institut National de la Recherche Agronomique (INRA)/Ecole
Nationale Vétérinaire de Toulouse (ENVT) 1225, Interactions Hôtes Agents
Pathogènes, ENVT, Toulouse, France3 Commissariat à l'Energie Atomique (CEA),
Service de Pharmacologie et d'Immunologie, DRM, CEA/Saclay, Gif sur Yvette,
France4 Bio-Rad, Research and Development Department, Marnes-la-Coquette,
France5 Hôpital Neurologique, Services de Neurochimie et de Pathologie,
Bron, France6 National Creutzfeldt-Jakob Disease Surveillance Unit, Division
of Pathology, University of Edinburgh, Western General Hospital, Edinburgh,
United Kingdom7 INSERM, Equipe Avenir, Maladies à Prions chez l'Homme,
Paris, France8 Neuropathology Laboratory, Salpêtrière Hospital, AP-HP,
Paris, France9 Service de Biochimie et Biologie Moléculaire, Hôpital
Lariboisière, Paris (Laboratoire associé au CNR “ATNC”) et EA 3621 Faculté
de Pharmacie, Paris, France10 Central Institute for Animal Disease Control
CIDC-Lelystad, Lelystad, The Netherlands

Abstract

Sporadic Creutzfeldt-Jakob disease (sCJD) cases are currently subclassified
according to the methionine/valine polymorphism at codon 129 of the PRNP
gene and the proteinase K (PK) digested abnormal prion protein (PrPres)
identified on Western blotting (type 1 or type 2). These biochemically
distinct PrPres types have been considered to represent potential distinct
prion strains. However, since cases of CJD show co-occurrence of type 1 and
type 2 PrPres in the brain, the basis of this classification system and its
relationship to agent strain are under discussion. Different brain areas
from 41 sCJD and 12 iatrogenic CJD (iCJD) cases were investigated, using
Western blotting for PrPres and two other biochemical assays reflecting the
behaviour of the disease-associated form of the prion protein (PrPSc) under
variable PK digestion conditions. In 30% of cases, both type 1 and type 2
PrPres were identified. Despite this, the other two biochemical assays found
that PrPSc from an individual patient demonstrated uniform biochemical
properties. Moreover, in sCJD, four distinct biochemical PrPSc subgroups
were identified that correlated with the current sCJD clinico-pathological
classification. In iCJD, four similar biochemical clusters were observed,
but these did not correlate to any particular PRNP 129 polymorphism or
western blot PrPres pattern. The identification of four different PrPSc
biochemical subgroups in sCJD and iCJD, irrespective of the PRNP
polymorphism at codon 129 and the PrPres isoform provides an alternative
biochemical definition of PrPSc diversity and new insight in the perception
of Human TSE agents variability.


snip...


Prion Strains and PrPSc Phenotype
Although prion strains can only be identified definitively by bioassay,
molecular in vitro tools to characterize PrPSc are more and more widely used
for the rapid identification of particular agents, such as BSE in cattle,
sheep, rodent and humans (vCJD) [20],[21]. This has come to be termed
“molecular strain typing” and although widely employed, the exact
relationship between PrPSc biochemistry and the biological properties of the
agents responsible remain to be determined. In sCJD, the presence of four
distinct PrPSc biochemical forms apparently correlated to
clinico-pathological phenotypes as defined by Parchi et al. [2] could be an
indication of the involvement of different TSE agents.

iCJD cases are a consequence of accidental human to human TSE transmission,
most likely representing transmission of sCJD. The identification in iCJD
cases of the four PrPSc signatures identified in sCJD is consistent with the
existence of distinct prions associated with these biochemical forms.

Three examples of human-to-human transmission of variant CJD through blood
transfusion have now been identified. While all blood donors were MM at
codon 129 PRNP, the recipients had either a MM (n = 2) or a MV genotype (n =
1). Despite this genotype difference there appears to have been conservation
of the disease phenotype and PrPres type in all “secondary” vCJD cases
[22]–[25]. These observations could suggest that in case of inter-human
transmission, difference in donor/recipient genotype could result in
un-altered abnormal PrP signature.

Our identification of MM GH iCJD cases harbouring similar PrPSc signature as
a VV1 sCJD case or of a VV dura mater iCJD case similar to MM2 sCJD might
indicate preservation of a specific PrPSc biochemical signature after human
to human transmission between individuals of different codon 129 genotypes.

Treatment with extracts of GH contaminated by CJD has lead to a high number
of iCJD cases in France and the UK. The codon 129 genotypes of the affected
individuals in the two countries differ, with the French cohort
predominantly MM and MV and the British cohort MV and VV [26]. In the
absence of any clear explanation for this finding, it was suggested that it
might be due to contamination of different batches of GH with different
prion strains from individuals of differing PRNP codon 129 genotypes. Our
identification of different biochemical forms of PrPSc in GH French patients
and in UK patients is consistent with this hypothesis. The variability
observed within the French GH cases could signify involvement of different
prion strains, consistent with multiple contaminated GH batches in the
French epidemic.

Conclusion
The identification in this study of different PrPSc species in CJD patients
with the same PRNP polymorphism at codon 129 and WB PrPres profile offers a
new perspective on our understanding of the relationship between PrP
biochemistry, prion disease phenotype and agent strain. We highlight two
novel approaches to analysing PrPSc in sCJD and iCJD and offer evidence that
these analyses provide potentially-strain associated information, which
appears to be lacking from the conventional WB assay.


snip...


SEE FULL TEXT ;


http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000029


Diagnosis and Reporting of Creutzfeldt-Jakob Disease

Singeltary, Sr et al. JAMA.2001; 285: 733-734.


Diagnosis and Reporting of Creutzfeldt-Jakob Disease

Since this article does not have an abstract, we have provided the first 150
words of the full text and any section headings.


To the Editor:

In their Research Letter, Dr Gibbons and colleagues1 reported that the
annual US death rate due to Creutzfeldt-Jakob disease (CJD) has been stable
since 1985. These estimates, however, are based only on reported cases, and
do not include misdiagnosed or preclinical cases. It seems to me that
misdiagnosis alone would drastically change these figures. An unknown number
of persons with a diagnosis of Alzheimer disease in fact may have CJD,
although only a small number of these patients receive the postmortem
examination necessary to make this diagnosis. Furthermore, only a few states
have made CJD reportable. Human and animal transmissible spongiform
encephalopathies should be reportable nationwide and internationally.

Terry S. Singeltary, Sr
Bacliff, Tex

1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob
disease in the United States: 1979-1998. JAMA. 2000;284:2322-2323. FREE FULL
TEXT


http://jama.ama-assn.org/cgi/content/extract/285/6/733?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=singeltary&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT

JOURNAL OF NEUROLOGY

MARCH 26, 2003

In light of the findings of Asante and Collinge et al, there

should be drastic measures to safeguard the medical and surgical arena

from sporadic CJDs and all human TSEs. I only ponder how many sporadic

CJDs in the USA are type 2 PrPSc?

http://www.neurology.org/cgi/eletters/60/2/176#535


TSS






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