PrPC Function

The cellular prion protein (PrPC) has been extensively investigated since its conformational isoform, the prion, was identified as the causative agent of prion disorders. PrPC is widely expressed in several tissues, reaching the highest levels in the nervous system. PrPC is a GPI-anchored protein, expressed on the external leaf of the cell membrane and composed of two domains: the folded C-terminal and the unfolded N-terminal domain. The N-terminal domain includes the octapeptide repeat region which is able to bind metal ions, particularly copper (both Cu(I) and Cu(II)) with high affinity and with lower affinity zinc and manganese. Moreover, PrPC supports the reduction from Cu(II) to Cu(I). To elucidate the function of PrPC, transgenic murine models have been developed by knocking out the PrPC-encoding gene, Prnp. Despite much effort, neither a physiological function nor a molecular mechanism has been clearly ascribed to PrPC. However, its high affinity for metal ions suggests that PrPC functions as a metal-binding protein. Indeed, PrPC-null mice (Prnp0/0) show impairments in different cellular pathways in which metal ions have a crucial role, for instance myelin formation and maintenance, modulation of neuron excitability, susceptibility to excitotoxic insult and recovery from ischemic stroke.

In an attempt to define PrPC molecular function as a metal-binding protein, in our lab we are investigating the neuroprotective PrPC function through NMDA receptor activity modulation as well as the role of PrPC in copper and iron homeostasis.