Browsing by Author "Ramos-Fernandez, Eva"

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    Physiological Control of Nitric Oxide in Neuronal BACE1 Translation by Heme-Regulated eIF2α Kinase HRI Induces Synaptogenesis
    (2015) ILL-Raga, Gerard; Tajes, Marta; Busquets-Garcia, Arnau; Ramos-Fernandez, Eva; Vargas, Lina M.; Bosch-Morato, Monica; Guivernau, Biuse; Valls-Comamala, Victoria; Eraso-Pichot, Abel; Guix, Francesc X.; Fandos, Cesar; Rosen, Mark D.; Rabinowitz, Michael H.; Maldonado, Rafael; Alvarez, Alejandra R.; Ozaita, Andres; Munoz, Francisco J.
    Aims: Hippocampus is the brain center for memory formation, a process that requires synaptogenesis. However, hippocampus is dramatically compromised in Alzheimer's disease due to the accumulation of amyloid beta-peptide, whose production is initiated by beta-site APP Cleaving Enzyme 1 (BACE1). It is known that pathological stressors activate BACE1 translation through the phosphorylation of the eukaryotic initiation factor-2 alpha (eIF2 alpha) by GCN2, PERK, or PKR kinases, leading to amyloidogenesis. However, BACE1 physiological regulation is still unclear. Since nitric oxide (NO) participates directly in hippocampal glutamatergic signaling, we investigated the neuronal role of the heme-regulated eukaryotic initiation factor eIF2 alpha kinase (HRI), which can bind NO by a heme group, in BACE1 translation and its physiological consequences. Results: We found that BACE1 is expressed on glutamate activation with NO being the downstream effector by triggering eIF2 alpha phosphorylation, as it was obtained by Western blot and luciferase assay. It is due to the activation of HRI by NO as assayed by Western blot and immunofluorescence with an HRI inhibitor and HRI siRNA. BACE1 expression was early detected at synaptic spines, contributing to spine growth and consolidating the hippocampal memory as assayed with mice treated with HRI or neuronal NO synthase inhibitors. Innovation: We provide the first description that HRI and eIF2 alpha are working in physiological conditions in the brain under the control of nitric oxide and glutamate signaling, and also that BACE1 has a physiological role in hippocampal function. Conclusion: We conclude that BACE1 translation is controlled by NO through HRI in glutamatergic hippocampal synapses, where it plays physiological functions, allowing the spine growth and memory consolidation. Antioxid. Redox Signal. 22, 1295-1307.
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    Wnt5a promotes hippocampal postsynaptic development and GluN2B-induced expression via the eIF2α HRI kinase
    (2021) Ramos-Fernandez, Eva; Arrazola, Macarena S.; Oliva, Carolina A.; Arredondo, Sebastian B.; Varela-Nallar, Lorena; Inestrosa, Nibaldo C.
    Wnt signaling plays a key role in neurodevelopment and neuronal maturation. Specifically, Wnt5a stimulates postsynaptic assemblies, increases glutamatergic neurotransmission and, through calcium signaling, generates nitric oxide (NO). Trying to unveil the molecular pathway triggering these postsynaptic effects, we found that Wnt5a treatment induces a time-dependent increases in the length of the postsynaptic density (PSD), elicits novel synaptic contacts and facilitates F-actin flow both in in vitro and ex vivo models. These effects were partially abolished by the inhibition of the Heme-regulated eukaryotic initiation factor 2 alpha (HRI) kinase, a kinase which phosphorylates the initiation translational factor eIF2 alpha. When phosphorylated, eIF2 alpha normally avoids the translation of proteins not needed during stress conditions, in order to avoid unnecessary energetic expenses. However, phosphorylated eIF2 alpha promotes the translation of some proteins with more than one open reading frame in its 5 ' untranslated region. One of these proteins targeted by Wnt-HRI-eIF2 alpha mediated translation is the GluN2B subunit of the NMDA receptor. The identified increase in GluN2B expression correlated with increased NMDA receptor function. Considering that NMDA receptors are crucial for excitatory synaptic transmission, the molecular pathway described here contributes to the understanding of the fast and plastic translational mechanisms activated during learning and memory processes.