The Cellular Prion Protein Interacts with the Tissue Non-Specific Alkaline Phosphatase in Membrane Microdomains of Bioaminergic Neuronal Cells

Abstract

Background

The cellular prion protein, PrP ^C, is GPI anchored and abundant in lipid rafts. The absolute requirement of PrP ^C in neurodegeneration associated to prion diseases is well established. However, the function of this ubiquitous protein is still puzzling. Our previous work using the 1C11 neuronal model, provided evidence that PrP ^C acts as a cell surface receptor. Besides a ubiquitous signaling function of PrP ^C, we have described a neuronal specificity pointing to a role of PrP ^C in neuronal homeostasis. 1C11 cells, upon appropriate induction, engage into neuronal differentiation programs, giving rise either to serotonergic (1C11 ^5-HT) or noradrenergic (1C11 ^NE) derivatives.

Methodology/Principal Findings

The neuronal specificity of PrP ^C signaling prompted us to search for PrP ^C partners in 1C11-derived bioaminergic neuronal cells. We show here by immunoprecipitation an association of PrP ^C with an 80 kDa protein identified by mass spectrometry as the tissue non-specific alkaline phosphatase (TNAP). This interaction occurs in lipid rafts and is restricted to 1C11-derived neuronal progenies. Our data indicate that TNAP is implemented during the differentiation programs of 1C11 ^5-HT and 1C11 ^NE cells and is active at their cell surface. Noteworthy, TNAP may contribute to the regulation of serotonin or catecholamine synthesis in 1C11 ^5-HT and 1C11 ^NE bioaminergic cells by controlling pyridoxal phosphate levels. Finally, TNAP activity is shown to modulate the phosphorylation status of laminin and thereby its interaction with PrP.

Conclusion/Significance

The identification of a novel PrP ^C partner in lipid rafts of neuronal cells favors the idea of a role of PrP in multiple functions. Because PrP ^C and laminin functionally interact to support neuronal differentiation and memory consolidation, our findings introduce TNAP as a functional protagonist in the PrP ^C-laminin interplay. The partnership between TNAP and PrP ^C in neuronal cells may provide new clues as to the neurospecificity of PrP ^C function.