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5 Structural Studies of Prion Proteins

Fred E. Cohen, Stanley B. Prusiner


Although many aspects of prion disease biology are unorthodox, perhaps the most fundamental paradox is posed by the coexistence of inherited, sporadic, and infectious forms of these diseases. Sensible molecular mechanisms for prion propagation must explain all three forms of prion diseases in a manner that is compatible with the formidable array of experimental data derived from histopathologic, biochemical, biophysical, human genetic, and transgenetic studies. In this chapter, we explore the phenomenologic constraints on models of prion replication with a specific emphasis on biophysical studies of prion protein structures. We examine how an inherited disease can also present as a sporadic or infectious illness in the context of the structural data on PrPs that are currently available.

The inherited prion diseases include Gerstmann-Sträussler-Scheinker disease (GSS), familial Creutzfeldt-Jakob disease (fCJD), and fatal familial insomnia (FFI). These patients present with characteristic clinical and neuropathologic findings as early as their third or fourth decade of life, and their family histories are compatible with an autosomal dominant pattern of inheritance (Chapter 13). Molecular genetic studies argue that these diseases are caused by mutations in the prion protein (PrP) gene based on high LOD scores for 5 of the 20 known mutations (Hsiao et al. 1989; Dlouhy et al. 1992; Petersen et al. 1992; Poulter et al. 1992; Gabizon et al. 1993). As with many inherited disorders, the pathogenesis of the inherited prion disease is due to the aberrant behavior of the protein encoded by the mutant PrP gene. The altered...

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