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PMID: 8978663 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Chemical chaperones interfere with the formation of scrapie prion protein.

The EMBO journal ·Vol. 15 ·No. 23 ·1996-12-02 ·Pages 6363-73

Tatzelt J, Prusiner SB, Welch WJ

Abstract

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.

MeSH Terms
Animals Brain/metabolism Cell Line Dimethyl Sulfoxide/pharmacology Glycerol/pharmacology Kinetics Methylamines/pharmacology Mice Molecular Chaperones Neuroblastoma Phospholipases PrPSc Proteins/biosynthesis,chemistry,drug effects Protein Folding Protein Structure, Secondary Reference Values Scrapie/metabolism Solubility Tumor Cells, Cultured
Chemicals
Methylamines Molecular Chaperones PrPSc Proteins Phospholipases trimethyloxamine Glycerol Dimethyl Sulfoxide
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Tatzelt J
Department of Neurology, University of California, San Francisco 94143, USA.
Prusiner S B
Welch W J
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
Published
1996-12-02
Pages
6363-73
Language
English
Region
England
NLM ID
8208664
PMCID
PMC452460
Subset
IM
External Links
PubMed source PMC Full Text View journal details
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