Pharmacological brake-release of mRNA translation enhances cognitive memory
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 signali...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2013-05-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/00498 |
| _version_ | 1818028323283927040 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Carmela Sidrauski |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T05:01:58Z |
| format | Article |
| id | doaj.art-8e9e1b8dba294563a7f482f53248b47c |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-12-10T05:01:58Z |
| publishDate | 2013-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-8e9e1b8dba294563a7f482f53248b47c2022-12-22T02:01:23ZengeLife Sciences Publications LtdeLife2050-084X2013-05-01210.7554/eLife.00498Pharmacological brake-release of mRNA translation enhances cognitive memoryCarmela Sidrauski0Diego Acosta-Alvear1Arkady Khoutorsky2Punitha Vedantham3Brian R Hearn4Han Li5Karine Gamache6Ciara M Gallagher7Kenny K-H Ang8Chris Wilson9Voytek Okreglak10Avi Ashkenazi11Byron Hann12Karim Nader13Michelle R Arkin14Adam R Renslo15Nahum Sonenberg16Peter Walter17Department 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 StatesDepartment 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 StatesDepartment of Biochemistry, McGill Cancer Center, Montreal, CanadaSmall Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United StatesSmall Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United StatesDepartment of Molecular Oncology, Genentech Inc, South San Francisco, United StatesDepartment of Psychology, McGill University, Montreal, CanadaDepartment 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 StatesSmall Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United StatesSmall Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United StatesDepartment 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 StatesDepartment of Molecular Oncology, Genentech Inc, South San Francisco, United StatesHelen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, United StatesDepartment of Psychology, McGill University, Montreal, CanadaSmall Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United StatesSmall Molecule Discovery Center and Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United StatesDepartment of Biochemistry, McGill Cancer Center, Montreal, CanadaDepartment 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 StatesPhosphorylation 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.https://elifesciences.org/articles/00498eIF2eIF2BATF4integrated stress responseunfolded protein responsememory consolidation |
| spellingShingle | 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 Pharmacological brake-release of mRNA translation enhances cognitive memory eLife eIF2 eIF2B ATF4 integrated stress response unfolded protein response memory consolidation |
| title | Pharmacological brake-release of mRNA translation enhances cognitive memory |
| title_full | Pharmacological brake-release of mRNA translation enhances cognitive memory |
| title_fullStr | Pharmacological brake-release of mRNA translation enhances cognitive memory |
| title_full_unstemmed | Pharmacological brake-release of mRNA translation enhances cognitive memory |
| title_short | Pharmacological brake-release of mRNA translation enhances cognitive memory |
| title_sort | pharmacological brake release of mrna translation enhances cognitive memory |
| topic | eIF2 eIF2B ATF4 integrated stress response unfolded protein response memory consolidation |
| url | https://elifesciences.org/articles/00498 |
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