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Pharmacological brake-release of mRNA translation enhances cognitive memory

2013; eLife Sciences Publications Ltd; Volume: 2; Linguagem: Inglês

10.7554/elife.00498

2050-084X

Carmela Sidrauski, Diego Acosta‐Alvear, Arkady Khoutorsky, P. Vedantham, Brian R. Hearn, Han Li, Karine Gamache, Ciara M Gallagher, Kenny K. H. Ang, Chris Wilson, Voytek Okreglak, Avi Ashkenazi, Byron Hann, Karim Nader, Michelle R. Arkin, Adam R. Renslo, Nahum Sonenberg, Peter Walter,

CRISPR and Genetic Engineering

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.