TSE-Associated Changes in PrP

In most TSE diseases, the same host gene encodes hoth PrP and PrP-res. In scrapie-infected neuroblastoma cells, at least, PrP is made from mature PrP (Borchelt et al, 1990) after it reaches the plasma membrane (Caughey and Raymond, 1991) (see Harris, this volume). The conversion site is likely to be either the cell surface and/or along an endocytic pathway to lysosomes (Caughey and Raymond, 1991 Caughey et al., 1991 Borchelt et al, 1992). PrP and PrP appear not to differ regularly in covalent structure (reviewed by Baldwin, this volume) however they can be discriminated in several other ways (reviewed in Caughey and Chesebro, 1997 Prusiner, 1998 Weissmann, 

Although harsh chemical treatments can denature PrP-res polymers in vitro and reduce infectivity, it is important from a therapeutic point of view to know whether PrP formation is reversible under physiological conditions. One analysis has indicated that under nondenaturing conditions favorable for the conversion reaction (pH 6, 200 mM KCl, 0.6% sarkosyl), no detectable solubilization/monomerization of prewashed 

Terms such as PrP-res and PrP are often used as if they represent a single conformational state or entity however, it is increasingly apparent that this is an oversimplification. TSE-associated PrP molecules can vary in resistance to proteolysis (Bessen and Marsh, 1994 Tagliavini et 

they might play a role in neuropathogenesis (Horiuchi and Caughey, 1999). Finally, manipulations of various recombinant and mutant forms of PrP have generated numerous forms of PrP that appear to share some, but not all, of the properties of bona fide TSE-associated PrP isolated from infected tissues. A current challenge is to understand which abnormal states of PrP are relevant to various aspects of TSE transmission and/or pathogenesis. The requirements may be different for infectious versus neurotoxic forms of PrP. With these uncertainties in mind, Weissmann has proposed the use of the term PrP to connote the putative infectious form of PrP, whatever it may be (Weissmann, 1991). 

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