Pharmacological brake-release of mRNA translation enhances cognitive memory

Sidrauski, Carmela; Acosta‐Alvear, Diego; Khoutorsky, Arkady; Vedantham, P.; Hearn, Brian R.; Li, Han; Gamache, Karine; Gallagher, Ciara M; Ang, Kenny Kean‐Hooi; Wilson, Chris; Okreglak, Voytek; Ashkenazi, Avi; Hann, Byron; Nader, Karim; Arkin, Michelle R.; Renslo, Adam R.; Sonenberg, Nahum; Walter, Peter

doi:10.7554/elife.00498

Cited by 593 publications

(656 citation statements)

References 46 publications

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“…It is therefore likely that sustained ISR activation may account for some of the metabolic deregulations associated with the use of HIV-PIs in patients. In this context, ISRIB, a small molecule that potently inhibits the effects of eIF2α phosphorylation (60)(61)(62), could become an interesting therapeutic option to alleviate ISR-associated metabolic alterations in HIV-PI-treated patients.…”

Section: Discussionmentioning

confidence: 99%

An inhibitor of HIV-1 protease modulates constitutive eIF2α dephosphorylation to trigger a specific integrated stress response

Gassart

Bujisic

Zaffalon

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Inhibitors of the HIV aspartyl protease [HIV protease inhibitors (HIV-PIs)] are the cornerstone of treatment for HIV. Beyond their well-defined antiretroviral activity, these drugs have additional effects that modulate cell viability and homeostasis. However, little is known about the virus-independent pathways engaged by these molecules. Here we show that the HIV-PI Nelfinavir decreases translation rates and promotes a transcriptional program characteristic of the integrated stress response (ISR). Mice treated with Nelfinavir display hallmarks of this stress response in the liver, including α subunit of translation initiation factor 2 (eIF2α) phosphorylation, activating transcription factor-4 (ATF4) induction, and increased expression of known downstream targets. Mechanistically, Nelfinavir-mediated ISR bypassed direct activation of the eIF2α stress kinases and instead relied on the inhibition of the constitutive eIF2α dephosphorylation and down-regulation of the phophatase cofactor CReP (Constitutive Repressor of eIF2α Phosphorylation; also known as PPP1R15B). These findings demonstrate that the modulation of eIF2α-specific phosphatase cofactor activity can be a rheostat of cellular homeostasis that initiates a functional ISR and suggest that the HIV-PIs could be repositioned as therapeutics in human diseases to modulate translation rates and stress responses.

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Section: Discussionmentioning

confidence: 99%

An inhibitor of HIV-1 protease modulates constitutive eIF2α dephosphorylation to trigger a specific integrated stress response

Gassart

Bujisic

Zaffalon

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…On the other hand, sustained aggregate stress may result in a disproportionate response. For example, the long-term down-regulation of translation caused by chronic ER stress can be especially detrimental to neuronal cells [99,100] which rely critically on ongoing translation for functionality. It will be crucial to unravel the mechanisms by which protein aggregation deregulates stress response pathways and undermines the cellular defense against toxic protein species.…”

Section: The Pn As a Target For Pharmacological Interventionmentioning

confidence: 99%

Proteostasis impairment in protein-misfolding and -aggregation diseases

Hipp

Park

Hartl

2014

Trends in Cell Biology

557

486

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Cells possess an extensive network of components to safeguard proteome integrity and maintain protein homeostasis (proteostasis). When this proteostasis network (PN) declines in performance, as may be the case during aging, newly synthesized proteins are no longer able to fold efficiently and metastable proteins lose their functionally active conformations, particularly under conditions of cell stress. Apart from loss-of-function effects, a critical consequence of PN deficiency is the accumulation of cytotoxic protein aggregates, which are also associated with many age-dependent neurodegenerative diseases and other medical disorders. Here we discuss recent evidence that the chronic production of aberrantly folded and aggregated proteins in these diseases is harmful by overtaxing PN capacity, setting in motion a vicious cycle of increasing proteome imbalance that eventually leads to PN collapse and cell death

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“…Thus, targeting the intra-axonal ISR or UPR might present a novel therapeutic approach to prevent or slow down disease progression in AD by inhibiting the local synthesis of ATF4. For example, recently small molecule inhibitors of PERK or eIF2α have been described that could potentially be used to uncouple axonal stress responses from retrograde neurodegenerative signals [84,85], thereby preventing the spread of AD pathology. By specifically targeting the UPR or eIF2α, these small molecule would not change the intra-axonal synthesis of potentially restorative proteins but instead act fairly selectively to suppress the translation of Atf4 and thereby prevent the retrograde spread of pathology without interfering with local, potentially prosurvival translation events.…”

Section: Stress Signaling In Axonsmentioning

confidence: 99%

Targeting Axonal Protein Synthesis in Neuroregeneration and Degeneration

Baleriola

Hengst

2015

Neurotherapeutics

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Localized protein synthesis is a mechanism by which morphologically polarized cells react in a spatially confined and temporally acute manner to changes in their environment. During the development of the nervous system intra-axonal protein synthesis is crucial for the establishment of neuronal connections. In contrast, mature axons have long been considered as translationally inactive but upon nerve injury or under neurodegenerative conditions specific subsets of mRNAs are recruited into axons and locally translated. Intra-axonally synthesized proteins can have pathogenic or restorative and regenerative functions, and thus targeting the axonal translatome might have therapeutic value, for example in the treatment of spinal cord injury or Alzheimer's disease. In the case of Alzheimer's disease the local synthesis of the stress response transcription factor activating transcription factor 4 mediates the long-range retrograde spread of pathology across the brain, and inhibition of local Atf4 translation downstream of the integrated stress response might interfere with this spread. Several molecular tools and approaches have been developed to target specifically the axonal translatome by either overexposing proteins locally in axons or, conversely, knocking down selectively axonally localized mRNAs. Many questions about axonal translation remain to be answered, especially with regard to the mechanisms establishing specificity but, nevertheless, targeting the axonal translatome is a promising novel avenue to pursue in the development for future therapies for various neurological conditions.

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Pharmacological brake-release of mRNA translation enhances cognitive memory

Cited by 593 publications

References 46 publications

An inhibitor of HIV-1 protease modulates constitutive eIF2α dephosphorylation to trigger a specific integrated stress response

An inhibitor of HIV-1 protease modulates constitutive eIF2α dephosphorylation to trigger a specific integrated stress response

Proteostasis impairment in protein-misfolding and -aggregation diseases

Targeting Axonal Protein Synthesis in Neuroregeneration and Degeneration

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