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    The prion protein constitutively controls neuronal store-operated Ca2+ entry through Fyn kinase

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    Author
    De Mario, A; Castellani, A; Peggion, C; Massimino, ML; Lim, D; Hill, AF; Sorgato, MC; Bertoli, A
    Date
    2015-10-28
    Source Title
    Frontiers in Cellular Neuroscience
    Publisher
    FRONTIERS MEDIA SA
    University of Melbourne Author/s
    Hill, Andrew
    Affiliation
    Biochemistry and Molecular Biology
    Metadata
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    Document Type
    Journal Article
    Citations
    De Mario, A., Castellani, A., Peggion, C., Massimino, M. L., Lim, D., Hill, A. F., Sorgato, M. C. & Bertoli, A. (2015). The prion protein constitutively controls neuronal store-operated Ca2+ entry through Fyn kinase. FRONTIERS IN CELLULAR NEUROSCIENCE, 9 (OCTOBER), https://doi.org/10.3389/fncel.2015.00416.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/257845
    DOI
    10.3389/fncel.2015.00416
    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.

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