Pharmacogenetic inhibition of eIF4E-dependent Mmp9 mRNA translation reverses fragile X syndrome-like phenotypes.

CG Gkogkas, A Khoutorsky, R Cao, SM Jafarnejad, M Prager-Khoutorsky, N Giannakas, A Kaminari, A Fragkouli, K Nader, TJ Price, BW Konicek, JR Graff, Athina K. Tzinia, Jean-Claude Lacaille, N Sonenberg

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Abstract

Fragile X syndrome (FXS) is the leading genetic cause of autism. Mutations in Fmr1 (fragile X mental retardation 1 gene) engender exaggerated translation resulting in dendritic spine dysmorphogenesis, synaptic plasticity alterations, and behavioral deficits in mice, which are reminiscent of FXS phenotypes. Using postmortem brains from FXS patients and Fmr1 knockout mice (Fmr1−/y), we show that phosphorylation of the mRNA 5′ cap binding protein, eukaryotic initiation factor 4E (eIF4E), is elevated concomitant with increased expression of matrix metalloproteinase 9 (MMP-9) protein. Genetic or pharmacological reduction of eIF4E phosphorylation rescued core behavioral deficits, synaptic plasticity alterations, and dendritic spine morphology defects via reducing exaggerated translation of Mmp9 mRNA in Fmr1−/y mice, whereas MMP-9 overexpression produced several FXS-like phenotypes. These results uncover a mechanism of regulation of synaptic function by translational control of Mmp-9 in FXS, which opens the possibility of new treatment avenues for the diverse neurological and psychiatric aspects of FXS.
Original languageEnglish
Pages (from-to)1742-1755
JournalCell Reports
Volume9
Issue number5
Early online date26 Nov 2014
DOIs
Publication statusPublished - 11 Dec 2014

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    Gkogkas, CG., Khoutorsky, A., Cao, R., Jafarnejad, SM., Prager-Khoutorsky, M., Giannakas, N., Kaminari, A., Fragkouli, A., Nader, K., Price, TJ., Konicek, BW., Graff, JR., Tzinia, A. K., Lacaille, J-C., & Sonenberg, N. (2014). Pharmacogenetic inhibition of eIF4E-dependent Mmp9 mRNA translation reverses fragile X syndrome-like phenotypes. Cell Reports, 9(5), 1742-1755. https://doi.org/10.1016/j.celrep.2014.10.064