Prion Diseases or Transmissible Spongiform Encephalopathies

Prion diseases are a group of transmissible neurodegenerative disorders including Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker syndrome (GSS) in humans, scrapie in sheep and goat, bovine spongiform encephalopathy (BSE) in cattle, and chronic wasting disease (CWD) in deer (review in Aguzzi et al. 2001; Collinge 2001; Prusiner et al. 1998; Weissmann et al. 1996). A hallmark of prion diseases is the accumulation of the misfolded and proteinase K-resistant scrapie prion protein (PrPSc), which co-purifies with the infectious scrapie agent (Bolton et al. 1982). Based on these and other studies, it was proposed that PrPSc is the essential component of the transmissible agent, termed prion (acronym for proteinaceous infectious particle) (Prusiner 1982). Experimental support for this model was provided recently: recombinant PrP expressed in bacteria and subsequently misfolded in vitro transmitted the disease to transgenic mice overexpressing the C-terminal domain (aa 89-231) of PrPC (Legname et al. 2004).

Considering a possible role of chaperones in the pathogenesis of prion diseases, different scenarios are conceivable. Given that chaperones recognize folding intermediates or misfolded conformers of PrP, such interactions could be beneficial or harmful to the cell: beneficial when chaperones promote the correct folding of PrP or target misfolded isoforms for degradation. Alternatively, an interaction of PrP with chaperones could enhance or facilitate a conformational transition into an aberrant conformation. In addition, one should consider the possibility that chaperones fail to prevent the formation and/or accumulation of aberrant PrP, either simply because they are not present in the critical cellular compartment or because they do not recognize PrP as a substrate. Interestingly, published data support any of these scenarios. In particular, different studies on pathogenic PrP mutants suggest that misfolded PrP conformers generated in the secretory pathway are not efficiently eliminated by cellular quality control pathways.

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