Effect of Congo red on wild-type and mutated prion proteins in cultured cells

Transmissible spongiform encephalopathies form a group of fatal neurodegene rative disorders that have the unique property of being infectious, sporadi c, or genetic in origin. Although some doubts remain on the nature of the r esponsible agent of these diseases, it is clear that a protein called PrPSc (which stands for the scrapie isoform of the prion protein) has a central role in their pathology. PrPSc represents a conformational variant of a nor mal protein of the host: the cellular isoform of the prion protein, or PrPC . Compounds such as glycosaminoglycans and Congo red (CR) have been shown t o interfere with both in vitro and in vivo PrPSc formation. It was hypothes ized that CR acts by overstabilizing the conformation of PrPSc molecules or by modifying trafficking of PrPC. Using transfected cells expressing 3F4-t agged mouse PrPs, we show here that CR does not interfere with conversion o f PrP molecules carrying pathogenic mutations, On the contrary, after incub ation with the drug, some of their properties, such as insolubility and pro tease resistance, are enhanced and are even acquired by the wild-type molec ule. This last observation suggests an alternative mechanism of action of C R and leads us to reconsider the relationship between the biochemical prope rties of PrP and conformational alteration of the protein.