PKR-Driven Isr Signaling Controls Synaptic Translation and Structural Plasticity in an Age-Dependent Manner

Authors

• Nicolás W Martínez
• Felipe Gómez
• Ariel Tapia-Godoy
• Juan Francisco Roa
• Fernanda Moreso-Contreras
• Yuwei Liu
• Claudia Jara
• Cheril Tapia-Rojas
• Iván Alfaro
• Mauro Costa-Mattioli
• Soledad Matus

Language

English

Publication Date

11-1-2025

Journal

Neurobiology of Disease

DOI

10.1016/j.nbd.2025.107113

PMID

40976378

Abstract

The 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.

Keywords

eIF-2 Kinase, Animals, Neuronal Plasticity, Synapses, Signal Transduction, Protein Biosynthesis, Mice, Eukaryotic Initiation Factor-2, Aging, Mice, Inbred C57BL, Male, Stress, Physiological, Neurons, PKR, PSD95, Proteostasis, Synapsin, eIF2α

Published Open-Access

yes

Recommended Citation

Martínez, Nicolás W; Gómez, Felipe; Tapia-Godoy, Ariel; et al., "PKR-Driven Isr Signaling Controls Synaptic Translation and Structural Plasticity in an Age-Dependent Manner" (2025). Faculty, Staff and Students Publications. 7264.
https://digitalcommons.library.tmc.edu/baylor_docs/7264