Prion Protein 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 investigated the neuroprotective PrPC function through NMDA receptor activity modulation as well as the role of PrPC in copper and iron homeostasis ([1], [2]).

Furthermore, by using a novel focal stimulation technique, we explored the potential function of PrPas a signaling molecule. In particular, we observed that soluble recombinant prion proteins (recPrP), when released by photolysis near the hippocampal growth cones (GC), induced neurite outgrowth and rapid GC turning towards the source in a concentration dependent [3].

1. Gasperini L, Meneghetti E, Pastore B, Benetti F, and Legname G. Antioxidants & Redox Signaling. March 2015, 22(9): 772-784.

2. Gasperini L, Meneghetti E, Legname G and Benetti F (2016) In Absence of the Cellular Prion Protein, Alterations in Copper Metabolism and Copper-Dependent Oxidase Activity Affect Iron Distribution. Front. Neurosci. 10:437. doi: 10.3389/fnins.2016.00437

3. Amin L, Nguyen X, Rolle I G, D'Este E, Giachin G, Tran H T, Šerbec V C, Cojoc D, Legname G, J Cell Sci 2016, Characterization of prion protein function by focal neurite stimulation, 129: 3878-3891; doi: 10.1242/jcs.183137