Pharmacological brake-release of mRNA translation enhances cognitive memory.

TitlePharmacological brake-release of mRNA translation enhances cognitive memory.
Publication TypeJournal Article
Year of Publication2013
AuthorsSidrauski C, Acosta-Alvear D, Khoutorsky A, Vedantham P, Hearn BR, Li H, Gamache K, Gallagher CM, Ang KK-H, Wilson C, Okreglak V, Ashkenazi A, Hann B, Nader K, Arkin MR, Renslo AR, Sonenberg N, Walter P
Date Published2013
KeywordsAcetamides, Animals, Cell Line, Cognition, Cyclohexylamines, Endoplasmic Reticulum, Eukaryotic Initiation Factor-1, Humans, Memory, Mice, Phosphorylation, Protein Biosynthesis, Protein Kinase Inhibitors, RNA, Messenger

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:

Alternate JournalElife
PubMed ID23741617
PubMed Central IDPMC3667625
Grant List / / Canadian Institutes of Health Research / Canada
/ / Howard Hughes Medical Institute / United States