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16 Some Strategies and Methods for the Study of Prions

Stanley B. Prusiner, Giuseppe Legname, Stephen J. Dearmond, Fred E. Cohen, Jiri Safar, Detlev Riesner, Kiyotoshi Kaneko


The discovery of the prion protein (PrP) by enriching fractions prepared from scrapie-infected hamster brains transformed research on the prion diseases. Prior to identification of PrP 27–30, the protease-resistant core of the misfolded, disease-causing PrP isoform (PrPSc), almost all studies of prions required bioassays. With the isolation of PrP 27–30, the tools of molecular cloning, genetics, immunology, cell biology, and structural biology could be applied to study prions.

Many different areas of prion disease can now be investigated using a wide variety of approaches. Recombinant PrP expressed in bacteria or mammalian cells can be isolated in large quantities and used for structural studies (Hornemann and Glockshuber 1996; Mehlhorn et al. 1996; Blochberger et al. 1997). The biology of PrPSc formation as well as the molecular pathogenesis of prion diseases can be studied in cultured cells and transgenic (Tg) mice. Similarly, potential therapeutics might be evaluated by measuring the inhibition of PrPSc formation in scrapie-infected cultured cells or Tg mice.

Immunoassays for PrPSc show great promise as tools to diagnose prion disease rapidly and to screen for subclinical cases in humans and domestic animals (Safar et al. 1998Safar et al. 2002; Biffiger et al. 2002). Because the particle-to-infectivity (P/I) ratio for prions is ~105 PrPSc molecules per ID50 unit (Prusiner et al. 1983), it may be possible to develop an immunoassay that is 10- to 100-fold more sensitive than bioassays in animals.

The biology of prions is sufficiently advanced that there are now several reasonably rational approaches available for the development...

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