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Abstract

1. Prion diseases include kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker disease (GSS), and fatal familia insomnia (FFI) of humans, as well as scrapie and bovine spongiform encephalopathy (BSE) of animals. 2. All these disorders involve conversion of the normal, cellular prion protein (PrPC) into the corresponding scrapie isoform (PrPSc). PrPC adopts a structure rich in alpha-helices and devoid of beta-sheet, in contrast to PrPSc, which has a high beta-sheet content and is resistant to limited digestion by proteases. That a conformational transition features in the conversion of PrPC into PrPSc implies that prion diseases are disorders of protein conformation. 3. This concept has been extended by our studies with heat shock proteins (Hsp), many of which are thought to function as molecular chaperones. We found that the induction of some Hsps but not others was profoundly altered in scrapie-infected cells and that the distribution of Hsp73 is unusual in these cells. 4. Whether the conversion of PrPC into PrPSc is assisted by molecular chaperones, or if the accumulation of the abnormally folded PrPSc is complexed with Hsps remains to be established.

Changes in HSP gene and protein expression in natural scrapie with brain damage

“…A recent report from our group identified the association between activation of the mitochondrial apoptosis pathway and early stages of PrP Sc deposition, whereas induction of the extrinsic pathway was related to reactive gliosis and neuronal loss [9]. During prion infection, gene and protein expression, principally of Hsp70 family members, is increased in different prion disease models [25-29]. …”

PrPSc Incorporation to Cells Requires Endogenous Glycosaminoglycan Expression

“…Consequently, considerable effort has been devoted to the identification of natural receptors for the prion proteins, both to understand the prion pathogenesis process and to reveal potential targets for therapeutic intervention. Among the proteins that were shown to bind PrP C were amyloid precursorlike protein 1 (5), stress-induced proteins, and the laminin receptors (6,7). Interestingly, antibodies to laminin receptors were shown to reduce the accumulation of PrP Sc in ScN2a cells (8).…”

Presenilin mutants subvert chaperone function

“…A variety of molecular chaperones can modulate the conformational state of yeast and mammalian prion proteins (see, for example, refs 12, 13). Furthermore, the inducibility of some heat-shock-responsive proteins (many of which are molecular chaperones) is altered in prion-infected cells, which may also exhibit an unusual distribution of Hsc73, a cytosolic homologue of BiP 14 …”