Neuronal pathophysiology featuring PrP^C and its control over Ca²⁺ metabolism

ABSTRACT

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.

KEYWORDS:

• Cellular prion protein
• PrP^C
• prions
• Ca²⁺
• store-operated Ca²⁺ entry
• glutamate receptors
• excitotoxicity
• knock-out mice
• neurons
• Aβ oligomers

Disclosure of potential conflicts of interest

Authors declare no potential conflict of interest.

Acknowledgments

Our gratitude goes to all collaborators whose work over the years has been essential to shed light on the PrP^C-Ca²⁺ connection.

Funding

Università degli Studi di Padova, PRAT CPDA158035/15 to A.B.

Università degli Studi di Padova, PRAT CPDA121988/12 to M.C.S.