Walter Lab

  • Walter Lab
  • Research
    • The Unfolded Protein Response and IRE1 Signaling in Health and Disease
    • Organellar quality control, dynamics, and inheritance
    • RNA processing in the unfolded protein response
    • The integrated stress response and its role in cognition
    • ATF6-branch signaling through regulated proteolysis
  • Lab Members
    • Current
    • Alumni
  • Contact Us
  • Social
  • Publications
  • News & Notes

Pharmacological brake-release of mRNA translation enhances cognitive memory

Sidrauski C, Acosta-Alvear D, Khoutorsky A, Vedantham P, Hearn B, Li H, Gamache K, Gallagher C, Ang K, Wilson C, Okreglak V, Ashkenazi A, Hann B, Nader K, Arkin M, Renslo A, Sonenberg N, Walter P. Pharmacological brake-release of mRNA translation enhances cognitive memory. eLife 2:e00498, 2013
(PMCID : PMC3667625) (PMID : 23741617) (PDF)

Abstract

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: http://dx.doi.org/10.7554/eLife.00498.001.


Deprecated: Hook genesis_footer_creds_text is deprecated since version 3.1.0! Use genesis_pre_get_option_footer_text instead. This filter is no longer supported. You can now modify your footer text using the Theme Settings. in /nas/content/live/wlabdemo/wp-includes/functions.php on line 5828

Copyright © 2023  Walter Lab | University of California, San Francisco | Howard Hughes Medical Institute