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Cell Rep. 2014 Dec 11;9(5):1742-1755. doi: 10.1016/j.celrep.2014.10.064. Epub 2014 Nov 26.

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

Author information

1
Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada. Electronic address: christos.gkogkas@ed.ac.uk.
2
Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada.
3
Center for Research in Neuroscience, McGill University, Montréal General Hospital, Montréal, QC H3G 1A4, Canada.
4
Institute of Biosciences and Applications, National Center for Scientific Research Demokritos, Agia Paraskevi, 15310 Athens, Greece.
5
Department of Psychology, McGill University, Montréal, QC H3A 1B1, Canada.
6
School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX 75080, USA.
7
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
8
GRSNC and Department of Neurosciences, Université de Montréal, Montréal, QC H3C 3J7, Canada.
9
Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada. Electronic address: nahum.sonenberg@mcgill.ca.

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.

PMID:
25466251
PMCID:
PMC4294557
DOI:
10.1016/j.celrep.2014.10.064
[Indexed for MEDLINE]
Free PMC Article

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