Physiological Control of Nitric Oxide in Neuronal <i>BACE1</i> Translation by Heme-Regulated eIF2α Kinase HRI Induces Synaptogenesis

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dc.contributor.authorILL-Raga, Gerard
dc.contributor.authorTajes, Marta
dc.contributor.authorBusquets-Garcia, Arnau
dc.contributor.authorRamos-Fernandez, Eva
dc.contributor.authorVargas, Lina M.
dc.contributor.authorBosch-Morato, Monica
dc.contributor.authorGuivernau, Biuse
dc.contributor.authorValls-Comamala, Victoria
dc.contributor.authorEraso-Pichot, Abel
dc.contributor.authorGuix, Francesc X.
dc.contributor.authorFandos, Cesar
dc.contributor.authorRosen, Mark D.
dc.contributor.authorRabinowitz, Michael H.
dc.contributor.authorMaldonado, Rafael
dc.contributor.authorAlvarez, Alejandra R.
dc.contributor.authorOzaita, Andres
dc.contributor.authorMunoz, Francisco J.
dc.date.accessioned2025-01-23T21:36:41Z
dc.date.available2025-01-23T21:36:41Z
dc.date.issued2015
dc.description.abstractAims: 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.
dc.fuente.origenWOS
dc.identifier.doi10.1089/ars.2014.6080
dc.identifier.eissn1557-7716
dc.identifier.issn1523-0864
dc.identifier.urihttps://doi.org/10.1089/ars.2014.6080
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/101567
dc.identifier.wosidWOS:000353718500001
dc.issue.numero15
dc.language.isoen
dc.pagina.final1307
dc.pagina.inicio1295
dc.revistaAntioxidants & redox signaling
dc.rightsacceso restringido
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titlePhysiological Control of Nitric Oxide in Neuronal <i>BACE1</i> Translation by Heme-Regulated eIF2α Kinase HRI Induces Synaptogenesis
dc.typeartículo
dc.volumen22
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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