PrPC associates with a multimolecular complex including LRP1 and glycosphingolipids within lipid rafts

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 (‘rafts’). Like other GPI-anchored proteins, most of PrPC molecules were found in lipid rafts from neural and non-neural cells. Recently, PrPC was identified as a high-affinity receptor for Aβ oligomers. Prion protein-mediated toxicity of Aβ oligomers requires lipid rafts and the transmembrane low density lipoprotein receptor-related protein-1 (LRP1). LRP1 is an endocytic and cell-signaling receptor for diverse ligands, which control the activity of LRP1 by directing the recruited co-receptors. LRP1 controls both the surface and intracellular trafficking of PrPC in neurons. Our results show that PrPC is strictly associated with gangliosides in microdomains of neuroblastoma cells. Scanning confocal analysis reveals a consistent co-localization between PrPC and GM1, as well as between TrkA and GM1, indicating the existence of a glycosphingolipid-enriched molecular complex. These data suggest that LRP1, PrPC and TrkA may function as part of a single system associated with lipid rafts, involved in receptor-mediated neuritogenic pathway. In addition, we confirmed by co-immunoprecipitation experiments a specific PrPC -ganglioside interaction. Moreover, signal transduction experiments on neuritogenic pathway were performed using human recombinant PrP (hPrPrec), and the results indicate a role for PrPC in cell signaling in neurons. We hypothesize that the ability of PrP to induce cell signaling might involve a multi receptor complex, in which LRP1, in association with other receptors, like TrkA receptor, plays a role in signal transduction within lipid rafts.These findings suggest that PrPC associates with a multimolecular complex, including, LRP1, TrkA and ganglioside GM1, which is dependent on the integrity of lipid raft and is involved in the neuritogenic signaling and trafficking.