The prion protein constitutively controls neuronal store-operated ca²⁺ entry through Fyn Kinase

The prion protein (PrP^C) is a cell surface glycoprotein mainly expressed in neurons, whose misfolded isoforms generate the prion responsible for incurable neurodegenerative disorders. Whereas PrP^C involvement in prion propagation is well established, PrP^C physiological function is still enigmatic despite suggestions that it could act in cell signal transduction by modulating phosphorylation cascades and Ca²⁺ homeostasis. Because PrP^C binds neurotoxic protein aggregates with high-affinity, it has also been proposed that PrPC acts as receptor for amyloid-b (Aβ) oligomers associated with Alzheimer’s disease (AD), and that PrP^C-Aβ binding mediates AD-related synaptic dysfunctions following activation of the tyrosine kinase Fyn. Here, use of gene-encoded Ca²⁺ probes targeting different cell domains in primary cerebellar granule neurons (CGN) expressing, or not, PrP^C, allowed us to investigate whether PrP^C regulates store-operated Ca²⁺ entry (SOCE) and the implication of Fyn in this control. Our findings show that PrP^C attenuates SOCE, and Ca²⁺ accumulation in the cytosol and mitochondria, by constitutively restraining Fyn activation and tyrosine phosphorylation of STIM1, a key molecular component of SOCE. This data establishes the existence of a PrP^C-Fyn-SOCE triad in neurons. We also demonstrate that treating cerebellar granule and cortical neurons with soluble Aβ_(1–42) oligomers abrogates the control of PrP^Cover Fyn and SOCE, suggesting a PrP^C-dependent mechanizm for Aβ-induced neuronal Ca²⁺ dyshomeostasis.