Pharmacological brake-release of mRNA translation enhances cognitive memory

被引：524

作者：

Sidrauski, Carmela ^{[1
,2
]}

Acosta-Alvear, Diego ^{[1
,2
]}

Khoutorsky, Arkady ^{[3
]}

Vedantham, Punitha ^{[4
,5
]}

Hearn, Brain R. ^{[4
,5
]}

Li, Han ^{[6
]}

Gamache, Karine ^{[7
]}

Gallagher, Ciara M. ^{[1
,2
]}

Ang, Kenny K-H ^{[4
,5
]}

Wilson, Chris ^{[4
,5
]}

Okreglak, Voytek ^{[1
,2
]}

Ashkenazi, Avi ^{[6
]}

Hann, Byron ^{[8
]}

Nader, Karim ^{[7
]}

Arkin, Michelle R. ^{[4
,5
]}

Renslo, Adam R. ^{[4
,5
]}

Sonenberg, Nahum ^{[3
]}

Walter, Peter ^{[1
,2
]}

机构：

[1] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA

[2] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA USA

[3] McGill Canc Ctr, Dept Biochem, Montreal, PQ, Canada

[4] Univ Calif San Francisco, Small Mol Discovery Ctr, San Francisco, CA 94143 USA

[5] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA USA

[6] Genentech Inc, Dept Mol Oncol, San Francisco, CA 94080 USA

[7] McGill Univ, Dept Psychol, Montreal, PQ, Canada

[8] Univ Calif San Francisco, Hellen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA

来源：

ELIFE | 2013年 / 2卷

基金：

加拿大健康研究院;

关键词：

UNFOLDED PROTEIN RESPONSE; GUANINE-NUCLEOTIDE EXCHANGE; ENDOPLASMIC-RETICULUM STRESS; SYNAPTIC PLASTICITY; MAMMALIAN-CELLS; FACTOR EIF2B; KINASE PERK; INITIATION; EIF2-ALPHA; PHOSPHORYLATION;

D O I：

10.7554/eLife.00498

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Phosphorylation of the alpha-subunit of initiation factor 2 (eIF2) controls protein synthesis by a conserved mechanism. In metazoa, distinct stress conditions activate different eIF2 alpha kinases (PERK, PKR, GCN2, and HRI) that converge on phosphorylating a unique serine in eIF2 alpha. This collection of signaling pathways is termed the 'integrated stress response' (ISR). eIF2 alpha 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 eIF2 alpha phosphorylation. ISRIB reduces the viability of cells subjected to PERK-activation by chronic endoplasmic reticulum stress. eIF2 alpha 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.

引用

页数：22

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