Trafficking of PrPCto mitochondrial raft-like microdomains during cell apoptosis

Abstract

The cellular form of prion protein (PrPC) is a highly conserved cell surface GPI-anchored glycoprotein that was identified in cholesterol-enriched, detergent-resistant microdomains named "rafts." The association with these specialized portions of the cell plasma membrane is required for conversion of PrPC to the transmissible spongiform encephalopathy-associated protease-resistant isoform. Usually, PrPC is reported to be a plasma membrane protein, however several studies have revealed PrPC as an interacting protein mainly with the membrane/organelles, as well as with cytoskeleton network. Recent lines of evidence indicated its association with ER lipid raft-like microdomains for a correct folding of PrPC, as well as for the export of the protein to the Golgi and proper glycosylation. During cell apoptosis, PrPC can undergo intracellular re-localization, via ER-mitochondria associated membranes (MAM) and microtubular network, to mitochondrial raft-like microdomains, where it induced the loss of mitochondrial membrane potential and cytochrome c release, after a contained raise of calcium concentration. We suggest that PrPC may play a role in the multimolecular signaling complex associated with cell apoptosis. Lipid rafts and their components may, thus, be investigated as pharmacological targets of interest, introducing a novel and innovative task in modern pharmacology, i.e., the development of glycosphingolipid targeted drugs. © 2012 Landes Bioscience.