Pharmacological brake-release of mRNA translation enhances cognitive memory

TLDR

Phosphorylation of eIF2α by stress‑activated kinases reduces global protein synthesis while permitting selective mRNA translation, a process known as the integrated stress response and implicated in memory consolidation. A small molecule ISRIB, discovered through a PERK signaling inhibitor screen, potently reverses eIF2α phosphorylation effects (IC50 = 5 nM). ISRIB enhances spatial and fear‑associated learning in mice, diminishes cell viability under chronic ER stress, and indicates that the ISR limits memory consolidation, offering therapeutic promise for cognitive disorders. DOI: http://dx.doi.org/10.7554/eLife.00498.001.

Abstract

Phosphorylation of the α-subunit of initiation factor 2 (eIF2) controls protein synthesis by a conserved mechanism. In metazoa, distinct stress conditions activate different eIF2α kinases (PERK, PKR, GCN2, and HRI) that converge on phosphorylating a unique serine in eIF2α. This collection of signaling pathways is termed the 'integrated stress response' (ISR). eIF2α phosphorylation diminishes protein synthesis, while allowing preferential translation of some mRNAs. Starting with a cell-based screen for inhibitors of PERK signaling, we identified a small molecule, named ISRIB, that potently (IC50 = 5 nM) reverses the effects of eIF2α phosphorylation. ISRIB reduces the viability of cells subjected to PERK-activation by chronic endoplasmic reticulum stress. eIF2α phosphorylation is implicated in memory consolidation. Remarkably, ISRIB-treated mice display significant enhancement in spatial and fear-associated learning. Thus, memory consolidation is inherently limited by the ISR, and ISRIB releases this brake. As such, ISRIB promises to contribute to our understanding and treatment of cognitive disorders. DOI:http://dx.doi.org/10.7554/eLife.00498.001.