Advancing Prion Science Guidance for the National Prion Research Program (2004) / Chapter Skim
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3 Basic Biomedical Research on Transmissible Spongiform Encephalopathies
3 Basic Biomedical Research on Transmissible Spongiform Encephalopathies
Pages 60-71
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From page 60... ...
However, the committee strongly believes that the fastest way to develop rapid, noninvasive, early-stage diagnostic tools for TSEs is through basic biomedical research that can fill gaps in the fundamental knowledge of prions and their disease-causing properties. The European experience provides evidence that applied research alone is insufficient.
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From page 61... ...
Antibody probes are increasingly being used to detect infectious agents in tissue, but their application to prion detection is limited because no independently validated antibody binds exclusively to PrPSc without prior digestion of PrPC. Of note, two different groups of investigators have reported separate antibodies specific to PrPSc (Korth et al., 1997; Paramithiotis et al., 20031.
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From page 62... ...
Nevertheless, the research community must do much more to obtain a comprehensive understanding of the structural differences between infectious and noninfectious PrP. MOLECULAR MECHANISMS OF PRION REPLICATION It is believed that both the conversion of cellular PrP to PrPSc and the accumulation of prions require the assistance of one or more molecules
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From page 63... ...
For instance, there may be a known antibody that binds specifically to a chaperone protein involved with PrP formation or accumulation. Ancillary or chaperoning factors could potentially amplify PrPSc, helping to overcome current limits to prion detection.
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From page 64... ...
Yet in a recent study, transgenic mice expressing human PrP and inoculated with the BSE agent manifested not only the expected vCJD phenotype, but also, surprisingly, the sCJD phenotype (Asante et al., 20021. The researchers suggest, in general, that TSE infections may involve multiple strains resulting in variable host responses.
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From page 65... ...
However, their experiment also showed that this disease-associated mutation differentially increased susceptibility to infection with human GSS-derived infectivity and simultaneously decreased susceptibility to several mouse scrapie strains. Thus, the study demonstrated that mutant PrP expression was an important genetic susceptibility factor, although it was unable to generate spontaneous infectivity in viva alone.
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From page 66... ...
Although most experts believe toxicity occurs at or near the cell membrane, new research in this area is challenging current theories. For example, studies by Ma and colleagues seem to indicate that cellular toxicity may occur in the cytoso!
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From page 67... ...
Drosophila and Caenorhabditis elegans have also proved to be superb models for the study of a variety of cellular and molecular processes (Hariharan and Haber, 2003) and should be exploited to study prion diseases.
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From page 68... ...
2002. BSE prions propagate as either variant CJDlike or sporadic CJD-like prion strains in transgenic mice expressing human prion protein.
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From page 69... ...
2003. Mutant PrP is delayed in its exit from the endoplasmic reticulum, but neither wild-type nor mutant PrP undergoes retrotranslocation prior to proteasomal degradation.
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From page 70... ...
introduced into murine PrP dramatically alters incubation time of transmissible spongiform encephalopathy. European Molecular Biology Organization Journal 18(23)
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From page 71... ...
Proceedings ofthe NationalAcademy of Sciences ofthe United States of America 97(1)
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