A role for intermolecular disulfide bonds in prion diseases?

The key event in prion diseases seems to be the conversion of the prion pro tein PrP from its normal cellular isoform (PrPC) to an aberrant "scrapie" i soform (PrPSc). Earlier studies have detected no covalent modification in t he scrapie isoform and have concluded that the PrPC --> PrPSc conversion is a purely conformational transition involving no chemical reactions. Howeve r, a reexamination of the available biochemical data suggests that the PrPC --> PrPSc conversion also involves a covalent reaction of the (sole) intra molecular disulfide bond of PrPC. Specifically, the data are consistent wit h the hypothesis that infectious prions are composed of PrPSc polymers link ed by intermolecular disulfide bonds. Thus, the PrPC --> PrPSc conversion m ay involve not only a conformational transition but also a thiol/disulfide exchange reaction between the terminal thiolate of such a PrPSc polymer and the disulfide bond of a PrPC monomer. This hypothesis seems to account for several unusual features of prion diseases.