Pharmacological brake-release of mRNA translation enhances cognitive memory
Carmela Sidrauski,
Diego Acosta-Alvear,
Arkady Khoutorsky,
Punitha 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
Affiliations
Carmela Sidrauski
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States
Diego Acosta-Alvear
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States
Arkady Khoutorsky
Department of Biochemistry, McGill Cancer Center, Montreal, Canada
Punitha Vedantham
Small Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
Brian R Hearn
Small Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
Han Li
Department of Molecular Oncology, Genentech Inc, South San Francisco, United States
Karine Gamache
Department of Psychology, McGill University, Montreal, Canada
Ciara M Gallagher
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States
Kenny K-H Ang
Small Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
Chris Wilson
Small Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
Voytek Okreglak
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States
Avi Ashkenazi
Department of Molecular Oncology, Genentech Inc, South San Francisco, United States
Byron Hann
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, United States
Karim Nader
Department of Psychology, McGill University, Montreal, Canada
Michelle R Arkin
Small Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
Adam R Renslo
Small Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
Nahum Sonenberg
Department of Biochemistry, McGill Cancer Center, Montreal, Canada
Peter Walter
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States
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.
