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 (PrP(C)) as they are converted into beta-sheets during the formation of the pathogenic isoform (PrP(Sc)). 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 PrP(Sc) 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 PrP(Sc) molecules in ScN2a cells, they did interfere with the formation of PrP(Sc) from newly synthesized PrP(C). We suggest that the chemical chaperones act to stabilize the alpha-helical conformation of PrP(C) and thereby prevent the protein from undergoing a conformational change to produce PrP(Sc). These observations provide further support for the idea that prions arise due to a change in protein conformation and reveal potential strategies for preventing PrP(Sc) formation.
Tatzelt
J
J
Department of Neurology, University of California, San Francisco 94143, USA.
Prusiner
S B
SB
Welch
W J
WJ
D000818:Animals; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D005990:Glycerol / Q000494:pharmacology; D007700:Kinetics; D008744:Methylamines / Q000494:pharmacology*; D051379:Mice; D018832:Molecular Chaperones; D009447:Neuroblastoma; D010740:Phospholipases; D018620:PrPSc Proteins / Q000096:biosynthesis* / Q000737:chemistry* / Q000187:drug effects; D017510:Protein Folding; D017433:Protein Structure, Secondary; D012016:Reference Values; D012608:Scrapie / Q000378:metabolism*; D012995:Solubility; D014407:Tumor Cells, Cultured
D008744:Methylamines; D018832:Molecular Chaperones; D018620:PrPSc Proteins; D010740:Phospholipases; C005855:trimethyloxamine; D005990:Glycerol; D004121:Dimethyl Sulfoxide