Trafficking of PrPsupc/sup to mitochondrial raft-like microdomains during cell apoptosis

摘要

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 citochrome 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.