Pharmacogenetic Inhibition of eIF4E-Dependent Mmp9 mRNA Translation Reverses Fragile X Syndrome-like Phenotypes

Christos G. Gkogkas, Arkady Khoutorsky, Ruifeng Cao, Seyed Mehdi Jafarnejad, Masha Prager-Khoutorsky, Nikolaos Giannakas, Archontia Kaminari, Apostolia Fragkouli, Karim Nader, Theodore J. Price, Bruce W. Konicek, Jeremy R. Graff, Athina K. Tzinia, Jean Claude Lacaille, Nahum Sonenberg

Research output: Contribution to journalArticle

96 Scopus citations

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. Fragile X syndrome (FXS) is caused by dysregulation of translation in the brain. Gkogkas etal. show that phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) is increased in FXS postmortem brains and Fmr1-/y mice. Downregulation of eIF4E phosphorylation in Fmr1-/y mice rescues defects in dendritic spine morphology, synaptic plasticity, and social interaction via normalization of MMP-9 expression.

Original languageEnglish (US)
Pages (from-to)1742-1755
Number of pages14
JournalCell reports
Volume9
Issue number5
DOIs
StatePublished - Dec 11 2014

Fingerprint Dive into the research topics of 'Pharmacogenetic Inhibition of eIF4E-Dependent Mmp9 mRNA Translation Reverses Fragile X Syndrome-like Phenotypes'. Together they form a unique fingerprint.

  • Cite this

    Gkogkas, C. G., Khoutorsky, A., Cao, R., Jafarnejad, S. M., Prager-Khoutorsky, M., Giannakas, N., Kaminari, A., Fragkouli, A., Nader, K., Price, T. J., Konicek, B. W., Graff, J. R., 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