Neuronal pathophysiology featuring PrPCand 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 (PrPC) in regulating neuronal Ca2+homeostasis, which could rationalize most of the wide range of functions ascribed to the protein. We have recently demonstrated that PrPCcontrols 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 PrPCprotects 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 PrPCwith Ca2+metabolism and also provide some speculative hints on the physiologic outcomes of this link. In addition, because PrPCis implicated in neurodegenerative diseases, including prion disorders and Alzheimer's disease, we will also discuss possible ways by which disruption of PrPC-Ca2+association could be mechanistically connected with these pathologies.