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

Emanuela Santini, Thu N. Huynh, Francesco Longo, So Yeon Koo, Edward Mojica, Laura D'Andrea, Claudia Bagni, Eric Klann

Research output: Contribution to journalArticle

Abstract

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and autismspectrum disorder. FXS is caused by silencing of the FMR1 gene, which encodes fragile X mental retardation protein (FMRP), an mRNAbinding 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 eIF4Emay be a strategy for treating FXS.

Original languageEnglish (US)
Article numbereaan0665
JournalScience Signaling
Volume10
Issue number504
DOIs
StatePublished - Nov 7 2017

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Fragile X Mental Retardation Protein
Eukaryotic Initiation Factor-4E
Fragile X Syndrome
Actins
Proteins
Protein Biosynthesis
p21-Activated Kinases
Actin Depolymerizing Factors
Metabotropic Glutamate Receptors
Dendritic Spines
Gene Silencing
Genes
Association reactions
Intellectual Disability
Data storage equipment
Hippocampus
Messenger RNA
Defects
Spine
Depression

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Reducing eIF4E-eIF4G interactions restores the balance between protein synthesis and actin dynamics in fragile X syndrome model mice. / Santini, Emanuela; Huynh, Thu N.; Longo, Francesco; Koo, So Yeon; Mojica, Edward; D'Andrea, Laura; Bagni, Claudia; Klann, Eric.

In: Science Signaling, Vol. 10, No. 504, eaan0665, 07.11.2017.

Research output: Contribution to journalArticle

Santini, Emanuela ; Huynh, Thu N. ; Longo, Francesco ; Koo, So Yeon ; Mojica, Edward ; D'Andrea, Laura ; Bagni, Claudia ; Klann, Eric. / Reducing eIF4E-eIF4G interactions restores the balance between protein synthesis and actin dynamics in fragile X syndrome model mice. In: Science Signaling. 2017 ; Vol. 10, No. 504.
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