Physiological role of the cellular prion protein

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 (PrPC) 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 PrPC function. Like other membrane proteins, PrPC is post-translationally processed in the endoplasmic reticulum and Golgi on its way to the cell surface after synthesis. Cell surface PrPC constitutively cycles between the plasma membrane and early endosomes via a clathrin-dependent mechanism, a pathway consistent with a suggested role for PrPC in cellular tracking of copper ions. Although PrP-/- mice have been reported to have only minor alterations in immune function, PrPC 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 PrPC 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 PrPC is required for self-renewal of haematopoietic stem cells. PrPC 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 PrPC in neurones. Although PrP-/-mice have a grossly normal neurological phenotype, even when neuronal PrPC 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 PrPC 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 PrPC in long-term memory open a challenging field.