Neuronal pathophysiology featuring PrPC and its control over Ca2+ metabolism.

Calcium (Ca²⁺) is an intracellular second messenger that ubiquitously masters remarkably diverse biological processes, including cell death. Growing evidence substantiates an involvement of the prion protein (PrP^C) in regulating neuronal Ca²⁺ homeostasis, which could rationalize most of the wide range of functions ascribed to the protein. We have recently demonstrated that PrP^C controls extracellular Ca²⁺ fluxes, and mitochondrial Ca²⁺ uptake, in neurons stimulated with glutamate (De Mario et al., J Cell Sci 2017; 130:2736-46), suggesting that PrP^C protects neurons from threatening Ca²⁺ overloads and excitotoxicity. In light of these results and of recent reports in the literature, here we review the connection of PrP^C with Ca²⁺ metabolism and also provide some speculative hints on the physiologic outcomes of this link. In addition, because PrP^C is implicated in neurodegenerative diseases, including prion disorders and Alzheimer's disease, we will also discuss possible ways by which disruption of PrP^C-Ca²⁺ association could be mechanistically connected with these pathologies.