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References online: prion





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J Thromb Haemost. 2003 Jul;1(7):1479-86.
Variant Creutzfeldt-Jakob disease and its transmission by blood.

Ironside JW, Head MW.

National Creutzfeldt-Jakob Disease Surveillance Unit, Division of Pathology, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, UK. j.w.ironsidd.ac.uk

Variant Creutzfeldt-Jakob disease (vCJD) is a novel acquired human prion disease resulting from human exposure to the agent causing bovine spongiform encephalopathy (BSE). vCJD differs from all other human prion diseases in that the disease-associated form of the prion protein and infectivity are present in lymphoid tissues throughout the body. Lymphoid tissues and lymphocytes are implicated in the peripheral pathogenesis of prion diseases (where infectivity may be detected during the preclinical phase of the illness), giving rise to concerns that blood and blood products may also contain infectivity, thus representing a possible source of iatrogenic spread of vCJD. These concerns have been reinforced by the recent transmission of BSE in an experimental sheep model by blood transfusion from an infected animal in the preclinical phase of the illness. Studies in other animal models suggest that most infectivity in blood may be cell-associated, with lower levels in the plasma, and there is evidence to indicate that any infectivity present may be reduced during the process of plasma fractionation. At present, the attempts to detect disease-associated prion protein and infectivity in buffy coat from vCJD patients have been negative, but these studies have been limited in size and in the sensitivity of the detection systems employed. Further studies are required to develop more sensitive means of detection of disease-associated prion protein in blood; such techniques could also be employed for screening purposes, both individually and to help ascertain more precisely the likely numbers of future cases of vCJD.


PMID:_12871283 [PubMed - in process]



J Biol Chem. 2003 Jul 18 [Epub ahead of print].
Cellular heparan sulfate participates in the metabolism of prions.

Kovalchuk O, Tzaban S, Tal Y, Horonchik L, Esko JD, Vlodavsky I, Taraboulos A.

Molecular Biology, Hebrew University-Hadassah Medical School, Jerusalem 91120.

During prion diseases the host protein PrPC is refolded into an abnormal prionconformer PrPSc. Histological and pharmacological data have suggested that glycosaminoglycans (GAGs) may be involved in the development of prion diseases. Here we present the first direct evidence that cellular GAGs play a role in the biogenesis of PrPSc in prion-infected ScN2a cells. When ScN2a cells were incubated with estradiol -D-xyloside to inhibit the glycosylation of proteoglycans, PrPSc was vastly reduced. Treating ScN2a-M cells with heparinase III, but not with heparinase I or chondroitinase ABC, caused a profound reduction of PrPSc. In contrast, neither the amount of PrPC nor its subcellular distribution were affected, as assayed by immunofluorescence microscopy and flotation procedures. In vitro treatment of ScN2a membranes with heparinase III at either neutral or acidic pH did not reduce the level of protease-resistant PrPSc. The inhibitor of sulfation, sodium chlorate, vastly reduces PrPSc in ScN2a cells (J Cell Physiol 157:319-325). Both soluble heparan sulfate and chondroitin sulfate partially restored the level of PrPSc in chlorate-treated cells. We conclude that heparinase III-sensitive, presumably undersulfated, cellular heparan sulfate play a significant role in the biogenesis of PrPSc in ScN2a cells.


PMID:_12871949 [PubMed - as supplied by publisher]



Biochemistry. 2003 Jul 29;42(29):8852-61.
Conformational transition occurring upon amyloid aggregation of the HET-s prion protein of Podospora anserina analyzed by hydrogen/deuterium exchange and mass spectrometry.

Nazabal A, Dos Reis S, Bonneu M, Saupe SJ, Schmitter JM.

CNRS FRE 2247 Institut Europeen de Chimie et Biologie, 16, Avenue Pey Berland 33607 Pessac, France. a.nazabaecb-polytechnique.u-bordeaux.fr

The [Het-s] infectious element of the filamentous fungus Podospora anserina corresponds to the prion form of the HET-s protein. HET-s (289 amino acids in length) aggregates into amyloid fibers in vitro. Such fibers obtained in vitro are infectious, indicating that the [Het-s] prion can propagate as a self-perpetuating amyloid aggregate of the HET-s protein. Previous analyses have suggested that only a limited region of the HET-s protein is involved in amyloid formation and prion propagation. To document the conformational transition occurring upon amyloid aggregation of HET-s, we have developed a method involving hydrogen/deuterium exchange monitored by MALDI-MS. In a first step, a peptide mass fingerprint of the protein was obtained, leading to 87% coverage of the HET-s primary structure. Amyloid aggregates of HET-s were obtained, and H/D exchange was monitored on the soluble and on the amyloid form of HET-s. This study revealed that in the soluble form of HET-s, the C-terminal region (spanning from residues 240-289) displays a high solvent accessibility. In sharp contrast, solvent accessibility is drastically reduced in that region in the amyloid form. H/D exchange rates and levels in the N-terminal part of the protein (residues 1-220) are comparable in the soluble and the aggregated state. These results indicate that amyloid aggregation of HET-s involves a conformational transition of the C-terminal part of the protein from a mainly disordered to an aggregated state in which this region is highly protected from hydrogen exchange.


PMID:_12873146



Neuroreport. 1999 Mar 17;10(4):723-9.
Microglial cells respond to amyloidogenic PrP peptide by the production of inflammatory cytokines.

Peyrin JM, Lasmezas CI, Haik S, Tagliavini F, Salmona M, Williams A, Richie D, Deslys JP, Dormont D.

CEA, Service de Neurovirologie (DSV/DRM), CRSSA, Institut Paris Sud sur les Cytokines, Fontenay-aux-Roses, France.

The scrapie isoform of the prion protein (PrPres) induces neurodegeneration and gliosis in the central nervous system. These features may be reproduced in vitro on exposure of neuronal and glial cultures to PrPres and the peptide HuPr P106-126. In the present study, we investigated the role of microglial cells and astrocytes in the pathological process by studying their molecular response to PrP 106-126 exposure. PrP 106-126 elicited a specific overproduction of pro-inflammatory cytokines IL1beta and IL6 in microglial cells (but not increased expression of TNFalpha, IL10, and TGFbeta1) and over-expression of GFAP in astrocytes. These effects were strictly dependent on the ability of the peptide to form amyloid fibrils. These data strongly suggest that microglial cells contribute to prion-related neurodegenerative processes by producing proinflammatory cytokines in the brain areas of amyloid PrP deposition.


PMID:_10208538

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