Physiological Control of Nitric Oxide in Neuronal BACE1 Translation by Heme-Regulated eIF2α Kinase HRI Induces Synaptogenesis.
Antioxidants & Redox Signaling. 2015-05-20; 22(15): 1295-1307
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1. Antioxid Redox Signal. 2015 May 20;22(15):1295-307. doi: 10.1089/ars.2014.6080.
Epub 2015 Mar 25.
Physiological Control of Nitric Oxide in Neuronal BACE1 Translation by
Heme-Regulated eIF2α Kinase HRI Induces Synaptogenesis.
Ill-Raga G(1), Tajes M, Busquets-García A, Ramos-Fernández E, Vargas LM,
Bosch-Morató M, Guivernau B, Valls-Comamala V, Eraso-Pichot A, Guix FX, Fandos C,
Rosen MD, Rabinowitz MH, Maldonado R, Alvarez AR, Ozaita A, Muñoz FJ.
(1)1 Laboratory of Molecular Physiology and Channelopathies, Universitat Pompeu
Fabra , Barcelona, Spain .
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 β-peptide, whose
production is initiated by β-site APP Cleaving Enzyme 1 (BACE1). It is known that
pathological stressors activate BACE1 translation through the phosphorylation of
the eukaryotic initiation factor-2α (eIF2α) 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 eIF2α 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 eIF2α 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 eIF2α 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
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.
PMID: 25706765 [Indexed for MEDLINE]