Prion protein (PrP) when misfolded is responsible for various neuronal disorders, including Creutzfeld-Jacob disease and "mad cow" disease. The normal physiological functions of PrP are less clear, although a role in cell recognition has been proposed. Santuccione et al. show that PrP and the neural cell adhesion molecule (NCAM) partially colocalize in membrane microdomains called lipid rafts in cultured hippocampal neurons and that the two proteins can be coimmunoprecipitated and chemically cross-linked. The abundance of NCAM140 and NCAM180, but not NCAM120 or the recognition molecule L1, in lipid rafts was reduced in brain homogenates from PrP—/— mice compared with that in wild-type mice. Triton X-100 extraction of cultured neurons to remove soluble, but not lipid raft-associated, proteins indicated that PrP contributed to the stability of NCAM in lipid rafts. Soluble PrP added to cultures from the PrP—/— mice also stabilized NCAM and stimulated the activation of the kinase Fyn. Thus, PrP appears to have a cis (on the same membrane) and trans contribution to recruit (trans) and stabilize (cis) NCAM in lipid rafts and trigger downstream signaling events. Soluble PrP or NCAM activation with antibodies or antibody fragments also induced the redistribution of NCAM into lipid rafts in wild-type cells based on an increase in lipid raft-associated NCAM. However, redistribution and Fyn activation triggered by NCAM antibodies was not observed in PrP—/— cells. A link between Fyn activation and PrP was also supported in vivo, where despite an increase in the overall abundance of Fyn in PrP—/— mouse brain homogenates, there was less phosphorylated (and activated) Fyn. Soluble PrP also triggered neurite outgrowth, and antibodies against PrP inhibited neurite outgrowth, possibly by interfering with cis PrP-NCAM interactions. PrP appears to have a dual role as a trans mediator of NCAM redistribution into lipid rafts and a cis mediator stabilizing NCAM in the lipid rafts and triggering downstream signaling through Fyn to stimulate neurite outgrowth.
A. Santuccione, V. Sytnyk, I. Leshchyns'ka, M. Schachner, Prion protein recruits its neuronal receptor NCAM to lipid rafts to activate p59fyn and to enhance neurite outgrowth. J. Cell. Biol. 169, 341-354 (2005). [Abstract] [Full Text]