Chemical chaperones interfere with the formation of scrapie prion protein

The fundamental event in prion diseases involves a conformational change in one or more of the alpha-helices of the cellular prion protein (PrPC) as they are converted into beta-sheets during the formation of the pathogenic isoform (PrPSc). Here, we show that exposure of scrapie-infected mouse neuroblastoma (ScN2a) cells to reagents known to stabilize proteins in their native conformation reduced the rate and extent of PrPSc formation. Such reagents include the cellular osmolytes glycerol and trimethylamine N-oxide (TMAO) and the organic solvent dimethylsulfoxide (DMSO), which we refer to as 'chemical chaperones' because of their influence on protein folding. Although the chemical chaperones did not appear to affect the existing population of PrPSc molecules in ScN2a cells, they did interfere with the formation of PrPSc from newly synthesized PrPC. We suggest that the chemical chaperones act to stabilize the alpha-helical conformation of PrPC and thereby prevent the protein from undergoing a conformational change to produce PrPSc, These observations provide further support for the idea that prions arise due to a change in protein conformation and reveal potential strategies for preventing PrPSc formation.