Prions Research Today is a free monthly online journal that collates and summarizes the latest research about Prions, including details on mad cow disease, scrapie, cjd.

Stress-protective signalling of prion protein is corrupted by scrapie prions.

Rambold AS, Müller V, Ron U, Ben-Tal N, Winklhofer KF, Tatzelt J

Department of Biochemistry, Neurobiochemistry, Ludwig-Maximilians-University Munich, München, Germany.

Studies in transgenic mice revealed that neurodegeneration induced by scrapie prion (PrP(Sc)) propagation is dependent on neuronal expression of the cellular prion protein PrP(C). On the other hand, there is evidence that PrP(C) itself has a stress-protective activity. Here, we show that the toxic activity of PrP(Sc) and the protective activity of PrP(C) are interconnected. With a novel co-cultivation assay, we demonstrate that PrP(Sc) can induce apoptotic signalling in PrP(C)-expressing cells. However, cells expressing PrP mutants with an impaired stress-protective activity were resistant to PrP(Sc)-induced toxicity. We also show that the internal hydrophobic domain promotes dimer formation of PrP and that dimerization of PrP is linked to its stress-protective activity. PrP mutants defective in dimer formation did not confer enhanced stress tolerance. Moreover, in chronically scrapie-infected neuroblastoma cells the amount of PrP(C) dimers inversely correlated with the amount of PrP(Sc) and the resistance of the cells to various stress conditions. Our results provide new insight into the mechanism of PrP(C)-mediated neuroprotection and indicate that pathological PrP conformers abuse PrP(C)-dependent pathways for apoptotic signalling.

Published 23 July 2008 in EMBO J, 27(14): 1974-84.
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Articles on Prions published 14 July 2008:

Inter-oligomer interactions of the human prion protein are modulated by the polymorphism at codon 129.   J Mol Biol, 381(1): 212-20.

The common polymorphism at codon 129 in the human prion protein (PrP) has been shown in many studies to influence not only the pathology of prion disease but also the misfolding propensity of PrP. Here we used NMR, CD and atomic force microscopy in solution to investigate differences in beta-oligomer (beta(O)) formation and inter-oligomer interaction depending on the polymorphism at codon 129. NMR investigations assigned the observable amide resonances to the beta(O) N-terminal segments, ... [Abstract] [Full-text]

Articles on Prions published 25 June 2008:

Cytoplasmic expression of mouse prion protein causes severe toxicity in Caenorhabditis elegans.   Biochem Biophys Res Commun, 372(4): 697-702.

To test if Caenorhabditis elegans could be established as a model organism for prion study, we created transgenic C. elegans expressing the cytosolic form of the mouse prion protein, MoPrP(23-231), which lacks the N-terminal signal sequence and the C-terminal glycosylphosphatidylinisotol (GPI) anchor site. We report here that transgenic worms expressing MoPrP(23-231)-CFP exhibited a wide range of distinct phenotypes: from normal growth and development, reduced mobility and development delay, ... [Abstract] [Full-text]

Coordinate regulation of bovine prion protein gene promoter activity by two Sp1 binding site polymorphisms.   Biochem Biophys Res Commun, 372(4): 530-5.

Relationships between insertion/deletion (Ins/Del) polymorphisms of the bovine prion protein gene (PRNP) promoter and bovine spongiform encephalopathy (BSE) susceptibility have been reported. Our previous study has shown that polymorphisms of -6C-->T included in the specific protein 1 (Sp1) site in the 5'-flanking region of bovine PRNP influence the promoter activity of bovine PRNP. The present study shows that 12 and 23bp Ins/Del polymorphisms in the upstream region and an additional ... [Abstract] [Full-text]

Articles on Prions published 23 June 2008:

GFP-tagged mutant prion protein forms intra-axonal aggregates in transgenic mice.   Neurobiol Dis, 31(1): 20-32.

A nine-octapeptide insertional mutation in the prion protein (PrP) causes a fatal neurodegenerative disorder in both humans and transgenic mice. To determine the precise cellular localization of this mutant PrP (designated PG14), we have generated transgenic mice expressing PG14-EGFP, a fluorescent fusion protein that can be directly visualized in vivo. Tg(PG14-EGFP) mice develop an ataxic neurological illness characterized by astrogliosis, PrP aggregation, and accumulation of a partially ... [Abstract] [Full-text]

Articles on Prions published 18 June 2008:

Genes contributing to prion pathogenesis.   J Gen Virol, 89: 1777-88.

Prion diseases are caused by conversion of a normally folded, non-pathogenic isoform of the prion protein (PrP(C)) to a misfolded, pathogenic isoform (PrP(Sc)). Prion inoculation experiments in mice expressing homologous PrP(C) molecules on different genetic backgrounds displayed different incubation times, indicating that the conversion reaction may be influenced by other gene products. To identify genes that contribute to prion pathogenesis, we analysed incubation times of prions in mice in ... [Abstract] [Full-text]

Articles on Prions published 13 June 2008:

Prion early kinetics revisited using a streptomycin-based PrP(res) extraction method.   Biochem Biophys Res Commun, 372(3): 429-33.

The use of streptomycin in the PrP(sc) detection procedures represents a new and attractive way to detect more PrP(sc), the best marker for the transmissible spongiform encephalopathies (TSEs). Actually, the streptomycin PrP(sc) aggregating property reported recently was established as beneficial in PrP(sc) detection using immunohistochemistry in diagnostic as well as in experimental conditions. The present study reports in details how to use advantageously this original streptomycin property ... [Abstract] [Full-text]

Articles on Prions published 11 June 2008:

Transmission and detection of prions in feces.   J Infect Dis, 198(1): 81-9.

In chronic wasting disease (CWD) in cervids and in scrapie in sheep, prions appear to be transmitted horizontally. Oral exposure to prion-tainted blood, urine, saliva, and feces has been suggested as the mode of transmission of CWD and scrapie among herbivores susceptible to these prion diseases. To explore the transmission of prions through feces, uninoculated Syrian hamsters (SHas) were cohabitated with or exposed to the bedding of SHas orally infected with Sc237 prions. Incubation times of ... [Abstract] [Full-text]

Articles on Prions published 10 June 2008:

Induced neuroprotection independently from PrPSc accumulation in a mouse model for prion disease treated with simvastatin.   Arch Neurol, 65(6): 762-75.

BACKGROUND: The misfolding and aggregation of specific proteins has emerged as a key feature of several neurodegenerative diseases. In prion diseases, progressive disease and neuronal loss are associated with the accumulation of PrP(Sc), the misfolded isoform of PrP(C). Previous in vitro studies suggest that cholesterol-lowering drugs inhibit the conversion of PrP(C) to PrP(Sc) and the accumulation of the latter, possibly through the disturbance of cholesterol-rich membrane domains (lipid ... [Abstract] [Full-text]

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