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PKR-driven ISR signaling controls synaptic translation and structural plasticity in an age-dependent manner

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dc.contributor.authorMartínez, Nicolás
dc.contributor.authorGómez, Felipe
dc.contributor.authorTapia, Ariel
dc.contributor.authorRoa, Juan
dc.contributor.authorMoreso, Fernanda
dc.contributor.authorLiu, Yuwei
dc.contributor.authorJara, Claudia
dc.contributor.authorTapia, Cheril
dc.contributor.authorAlfaro, Ivan
dc.contributor.authorCosta, Mauro
dc.contributor.authorMatus, Soledad
dc.date.accessioned2026-09-07T18:53:41Z
dc.date.available2026-09-07T18:53:41Z
dc.date.issued2025
dc.description.abstractThe integrated stress response (ISR) modulates protein homeostasis in response to both intracellular and extracellular signals. The four kinases involved in the ISR all phosphorylate the same target, the alpha subunit of eukaryotic initiation factor 2 (eIF2α), to integrate various stress signals, thereby regulating cell fate. The activation of the ISR reprograms the proteome by inhibiting general protein synthesis while increasing the translation of specific mRNAs. In the brain, the ISR regulates the type of synaptic plasticity necessary for forming long-term memory. More importantly, the activation of the ISR has emerged as a causal mechanism underlying cognitive decline associated with a wide range of neurological disorders, prompting several pharmaceutical companies to target the ISR to promote brain health. However, whether the ISR acts at specific localities within neurons, including synapses, remains unclear. Here, we examined the presence, activity, and spatial arrangement of the ISR branch driven by the double-stranded RNA-dependent protein kinase (PKR) (PKR-eIF2α axis) in synapses and assessed the role of PKR in maintaining synaptic proteostasis over time. Our findings demonstrate that both PKR and eIF2α are localized at synapses, where a dynamic PKR-eIF2α axis regulates synaptic size and the abundance of synaptic proteins in an age-dependent manner. Moreover, PKR deficiency leads to an increase in protein synthesis in synapse-enriched fractions. Thus, the PKR branch of the ISR serves as a new regulator of synaptic structural plasticity.
dc.description.versionVersión Publicada
dc.identifier.citationMartínez NW, Gómez F, Tapia-Godoy A, Roa JF, Moreso-Contreras F, Liu Y, Jara C, Tapia-Rojas C, Alfaro I, Costa-Mattioli M, Matus S. PKR-driven ISR signaling controls synaptic translation and structural plasticity in an age-dependent manner. Neurobiol Dis. 2025 Nov;216:107113. doi: 10.1016/j.nbd.2025.10711
dc.identifier.doihttps://doi.org/10.1016/j.nbd.2025.107113
dc.identifier.urihttps://hdl.handle.net/11447/11074
dc.language.isoen
dc.subjectNeurons
dc.subjectPKR
dc.subjectPSD95
dc.subjectProteostasis
dc.subjectSynapsin
dc.subjecteIF2α
dc.titlePKR-driven ISR signaling controls synaptic translation and structural plasticity in an age-dependent manner
dc.typeArticle
dcterms.accessRightsAcceso Abierto
dcterms.sourceNeurobiology of Disease
dspace.entity.typePublication
relation.isAuthorOfPublication57eddc30-b34b-4af7-869d-ed5152bfa3d6
relation.isAuthorOfPublication.latestForDiscovery57eddc30-b34b-4af7-869d-ed5152bfa3d6

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