15 Some Strategies and Methods for the Study of Prions

Abstract

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 scrapie prion protein (PrP^Sc), almost all studies of prions required bioassays. With the isolation of PrP 27–30 came the ability to apply the tools of molecular cloning, genetics, immunology, cell biology, and structural biology.

Many different areas of the prion diseases 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 (Mehlhorn et al. 1996; Blochberger et al. 1997). The biology of PrP^Sc 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 PrP^Sc formation in scrapie-infected cultured cells or Tg mice. The biology of prions is sufficiently advanced that there are now three reasonably rational approaches available for the development of effective therapies and preventive measures in humans. First, drugs that alter the conformation of PrP^Sc and allow the cell to degrade it might prove to be efficacious. Second, drugs that block the formation of nascent PrP^Sc by interfering with the binding of PrP^C to PrP^Sc might also prove effective. Third, pharmacotherapeutics that disrupt the binding of PrP^C to protein X may prove the most effective of all the approaches currently available (Kaneko et al. 1997c). In...