Pharmacological brake-release of mRNA translation enhances cognitive memory
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- Carmela Sidrauski
- Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
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- Diego Acosta-Alvear
- Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
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- Arkady Khoutorsky
- Department of Biochemistry, McGill Cancer Center, Montreal, Canada
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- Punitha Vedantham
- Small Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
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- Brian R Hearn
- Small Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
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- Han Li
- Department of Molecular Oncology, Genentech Inc, South San Francisco, United States
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- Karine Gamache
- Department of Psychology, McGill University, Montreal, Canada
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- Ciara M Gallagher
- Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
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- Kenny K-H Ang
- Small Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
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- Chris Wilson
- Small Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
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- Voytek Okreglak
- Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
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- Avi Ashkenazi
- Department of Molecular Oncology, Genentech Inc, South San Francisco, United States
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- Byron Hann
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, United States
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- Karim Nader
- Department of Psychology, McGill University, Montreal, Canada
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- Michelle R Arkin
- Small Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
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- Adam R Renslo
- Small Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
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- Nahum Sonenberg
- Department of Biochemistry, McGill Cancer Center, Montreal, Canada
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- Peter Walter
- Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
説明
<jats:p>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.</jats:p>
収録刊行物
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- eLife
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eLife 2 e00498-, 2013-05-28
eLife Sciences Publications, Ltd
