title: The prion protein constitutively controls neuronal store-operated Ca(2+) entry through Fyn kinase.
abstract: 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 Ca(2+) homeostasis. Because PrP(C) binds neurotoxic protein aggregates with high-affinity, it has also been proposed that PrP(C) acts as receptor for amyloid-β (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 Ca(2+) 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 Ca(2+) entry (SOCE) and the implication of Fyn in this control. Our findings show that PrP(C) attenuates SOCE, and Ca(2+) 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(C) over Fyn and SOCE, suggesting a PrP(C)-dependent mechanizm for Aβ-induced neuronal Ca(2+) dyshomeostasis.
authors.affiliation: Department of Biomedical Science, University of Padova Padova, Italy.
authors.forename: Agnese
authors.initials: A
authors.lastname: De Mario
authors.affiliation: Department of Biomedical Science, University of Padova Padova, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Castellani
authors.affiliation: Department of Biomedical Science, University of Padova Padova, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Peggion
authors.affiliation: CNR Neuroscience Institute, University of Padova Padova, Italy.
authors.forename: Maria Lina
authors.initials: ML
authors.lastname: Massimino
authors.affiliation: Department of Pharmaceutical Science, University of Piemonte Orientale Novara, Italy.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Lim
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University Melbourne, VIC, Australia.
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Hill
authors.affiliation: Department of Biomedical Science, University of Padova Padova, Italy ; CNR Neuroscience Institute, University of Padova Padova, Italy.
authors.forename: M Catia
authors.initials: MC
authors.lastname: Sorgato
authors.affiliation: Department of Biomedical Science, University of Padova Padova, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bertoli
keywords: Abeta oligomers; Alzheimer’s disease; Ca2+; Fyn kinase; STIM1; cerebellar granule neurons; prion protein; store-operated Ca2+ entry