Neuronal pathophysiology featuring PrP and its control over Ca metabolism.

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