Physiological role of the cellular prion protein
Résumé
The prion protein (PrP) plays a key role in the pathogenesis of prion diseases. However, the normal function of the protein remains unclear. The cellular isoform (PrP$^{C})$ is expressed most abundantly in the brain, but has also been detected in other non-neuronal tissues as diverse as lymphoid cells, lung, heart, kidney, gastrointestinal tract, muscle, and mammary glands. Cell biological studies of PrP contribute to our understanding of PrP$^{\rm C}$ function. Like other membrane proteins, PrP$^{\rm C}$ is post-translationally processed in the endoplasmic reticulum and Golgi on its way to the cell surface after synthesis. Cell surface PrP$^{\rm C}$ constitutively cycles between the plasma membrane and early endosomes via a clathrin-dependent mechanism, a pathway consistent with a suggested role for PrP$^{\rm C}$ in cellular trafficking of copper ions. Although PrP$^{-/-}$ mice have been reported to have only minor alterations in immune function, PrP$^{\rm C}$ is up-regulated in T cell activation and may be expressed at higher levels by specialized classes of lymphocytes. Furthermore, antibody cross-linking of surface PrP$^{\rm C}$ modulates T cell activation and leads to rearrangements of lipid raft constituents and increased phosphorylation of signaling proteins. These findings appear to indicate an important but, as yet, ill-defined role in T cell function. Recent work has suggested that PrP$^{\rm C}$ is required for self-renewal of haematopoietic stem cells. PrP$^{\rm C}$ is highly expressed in the central nervous system, and since this is the major site of prion pathology, most interest has focused on defining the role of PrP$^{\rm C}$ in neurones. Although PrP$^{-/-}$ mice have a grossly normal neurological phenotype, even when neuronal PrP$^{\rm C}$ is knocked out postnatally, they do have subtle abnormalities in synaptic transmission, hippocampal morphology, circadian rhythms, and cognition and seizure threshold. Other postulated neuronal roles for PrP$^{\rm C}$ include copper-binding, as an anti- and conversely, pro-apoptotic protein, as a signaling molecule, and in supporting neuronal morphology and adhesion. The prion protein may also function as a metal binding protein such as copper, yielding cellular antioxidant capacity suggesting a role in the oxidative stress homeostasis. Finally, recent observations on the role of PrP$^{\rm C}$ in long-term memory open a challenging field.
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