Calnexin inhibits thermal aggregation and neurotoxicity of prion protein

Abstract

Prion diseases are fatal neurodegenerative disorder associated with the conversion of the cellular isoform of the prion protein (PrPC) into the infectious scrapie isoform (PrPSc). Deposition of misfolded prion proteins (PrP) on certain regions of brain can result in prion diseases. As a membrane-bound chaperone of the endoplasmic reticulum (ER), calnexin ensures the proper folding and quality control of newly synthesized proteins. Using purified components in vitro, calnexin associated with many proteins and suppresses their thermal aggregation effectively. We for the first time analyzed PrP-calnexin interaction. The immunoprecipitation, confocal microscope and native polyacrylamide-gel electrophoresis results indicated that calnexin could bind PrP both in vitro and in vivo. The turbidity result showed that calnexin could supress thermal aggregation of PrP. MTT, flow cytometry (FCM) and caspase activity studies demonstrated that calnexin prevent caspase-3-mediated cytotoxicity induced by PrP. These results implied that calnexin is potentially beneficial for the resistance of prion diseases. © 2010 Wiley-Liss, Inc.