Reducing eIF4E-eIF4G interactions restores the balance between protein synthesis and actin dynamics in fragile X syndrome model mice.

Details

Serval ID
serval:BIB_60DD9AD64B2D
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Reducing eIF4E-eIF4G interactions restores the balance between protein synthesis and actin dynamics in fragile X syndrome model mice.
Journal
Science signaling
Author(s)
Santini E., Huynh T.N., Longo F., Koo S.Y., Mojica E., D'Andrea L., Bagni C., Klann E.
ISSN
1937-9145 (Electronic)
ISSN-L
1945-0877
Publication state
Published
Issued date
07/11/2017
Peer-reviewed
Oui
Volume
10
Number
504
Pages
NA
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and autism spectrum disorder. FXS is caused by silencing of the <i>FMR1</i> gene, which encodes fragile X mental retardation protein (FMRP), an mRNA-binding protein that represses the translation of its target mRNAs. One mechanism by which FMRP represses translation is through its association with cytoplasmic FMRP-interacting protein 1 (CYFIP1), which subsequently sequesters and inhibits eukaryotic initiation factor 4E (eIF4E). CYFIP1 shuttles between the FMRP-eIF4E complex and the Rac1-Wave regulatory complex, thereby connecting translational regulation to actin dynamics and dendritic spine morphology, which are dysregulated in FXS model mice that lack FMRP. Treating FXS mice with 4EGI-1, which blocks interactions between eIF4E and eIF4G, a critical interaction partner for translational initiation, reversed defects in hippocampus-dependent memory and spine morphology. We also found that 4EGI-1 normalized the phenotypes of enhanced metabotropic glutamate receptor (mGluR)-mediated long-term depression (LTD), enhanced Rac1-p21-activated kinase (PAK)-cofilin signaling, altered actin dynamics, and dysregulated CYFIP1/eIF4E and CYFIP1/Rac1 interactions in FXS mice. Our findings are consistent with the idea that an imbalance in protein synthesis and actin dynamics contributes to pathophysiology in FXS mice, and suggest that targeting eIF4E may be a strategy for treating FXS.
Keywords
Actins/metabolism, Animals, Dendritic Spines/drug effects, Disease Models, Animal, Eukaryotic Initiation Factor-4E/antagonists & inhibitors, Eukaryotic Initiation Factor-4E/genetics, Eukaryotic Initiation Factor-4E/metabolism, Eukaryotic Initiation Factor-4G/antagonists & inhibitors, Eukaryotic Initiation Factor-4G/genetics, Eukaryotic Initiation Factor-4G/metabolism, Fragile X Mental Retardation Protein/genetics, Fragile X Mental Retardation Protein/metabolism, Fragile X Syndrome/drug therapy, Fragile X Syndrome/metabolism, Hippocampus/drug effects, Hippocampus/physiopathology, Hydrazones/pharmacology, Hydrazones/therapeutic use, Male, Memory Disorders/drug therapy, Mice, Mice, Inbred C57BL, Nerve Tissue Proteins/genetics, Nerve Tissue Proteins/metabolism, Thiazoles/pharmacology, Thiazoles/therapeutic use
Pubmed
Web of science
Open Access
Yes
Create date
15/11/2017 8:57
Last modification date
20/08/2019 14:18
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