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

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Science Signaling  07 Nov 2017:
Vol. 10, Issue 504, eaan0665
DOI: 10.1126/scisignal.aan0665

Finding balance between translation and Rac1 signaling in FXS

Loss of the mRNA translation repressor FMRP in patients with fragile X syndrome (FXS) causes the increased translation of FMRP target transcripts, neurological dysfunction, and intellectual disability. Santini et al. found that through its interaction with the scaffolding protein CYFIP1, FMRP sequesters the translation-initiating factor eIF4E and tempers the CYFIP1-mediated facilitation of Rac1-cofilin signaling. Thus, loss of FMRP increased the abundance of eIF4G-bound eIF4E, CYFIP1-Rac1 complexes, and inactivated cofilin, thereby impairing the actin polymerization dynamics necessary for synaptic plasticity and learning. The compound 4EGI-1, which inhibits the formation of eIF4E-mediated translational machinery, reduced protein synthesis and restored a balance with actin dynamics, as well as improved hippocampal synaptic function and dendritic morphology and learning behaviors in FXS model mice. Thus, inhibiting eIF4E-mediated protein synthesis may be therapeutic in FXS patients.

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