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


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.; Copyright



Fragile X syndrome, Eukaryotic Initiation Factor-4E (eIF4E), Phosphorylation, Mice--Diseases--Research, Matrix Metalloproteinase 9, Messenger RNA

"This work was supported by a CIHR operating grant to N.S. (MOP-114994) and J.-C.L. (MOP-125985), the Azrieli Foundation and Brain Canada team grant to N.S. and J.-C.L., the Fonds de la Recherche du Québe-Santé (grant to J.-C.L. FRQS; Groupe de Recherche sur le Système Nerveux Central). J.-C.L. is the recipient of the Canada Research Chair in Cellular and Molecular Neurophysiology. C.G.G. received support from the Wellcome Trust-University of Edinburgh Institutional Strategic Support Fund. Human tissue was obtained from the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland, Baltimore and the Harvard Brain Tissue Resource Center (grant number R24-MH 068855)."


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