title: Pharmacogenetic inhibition of eIF4E-dependent Mmp9 mRNA translation reverses fragile X syndrome-like phenotypes.
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.
authors.affiliation: Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada. Electronic address: christos.gkogkas@ed.ac.uk.
authors.forename: Christos G
authors.initials: CG
authors.lastname: Gkogkas
authors.affiliation: Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada.
authors.forename: Arkady
authors.initials: A
authors.lastname: Khoutorsky
authors.affiliation: Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada.
authors.forename: Ruifeng
authors.initials: R
authors.lastname: Cao
authors.affiliation: Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada.
authors.forename: Seyed Mehdi
authors.initials: SM
authors.lastname: Jafarnejad
authors.affiliation: Center for Research in Neuroscience, McGill University, Montréal General Hospital, Montréal, QC H3G 1A4, Canada.
authors.forename: Masha
authors.initials: M
authors.lastname: Prager-Khoutorsky
authors.affiliation: Institute of Biosciences and Applications, National Center for Scientific Research Demokritos, Agia Paraskevi, 15310 Athens, Greece.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Giannakas
authors.affiliation: Institute of Biosciences and Applications, National Center for Scientific Research Demokritos, Agia Paraskevi, 15310 Athens, Greece.
authors.forename: Archontia
authors.initials: A
authors.lastname: Kaminari
authors.affiliation: Institute of Biosciences and Applications, National Center for Scientific Research Demokritos, Agia Paraskevi, 15310 Athens, Greece.
authors.forename: Apostolia
authors.initials: A
authors.lastname: Fragkouli
authors.affiliation: Department of Psychology, McGill University, Montréal, QC H3A 1B1, Canada.
authors.forename: Karim
authors.initials: K
authors.lastname: Nader
authors.affiliation: School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX 75080, USA.
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Price
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Konicek
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Graff
authors.affiliation: Institute of Biosciences and Applications, National Center for Scientific Research Demokritos, Agia Paraskevi, 15310 Athens, Greece.
authors.forename: Athina K
authors.initials: AK
authors.lastname: Tzinia
authors.affiliation: GRSNC and Department of Neurosciences, Université de Montréal, Montréal, QC H3C 3J7, Canada.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Lacaille
authors.affiliation: Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada. Electronic address: nahum.sonenberg@mcgill.ca.
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors; D000818:Animals; D001321:Autistic Disorder / Q000201:enzymology; D001572:Benzofurans / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000201:enzymology; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D000073840:Copper-Transporting ATPases; D049229:Dendritic Spines / Q000473:pathology; D004790:Enzyme Induction / Q000187:drug effects; D039561:Eukaryotic Initiation Factor-4E / Q000502:physiology*; D005260:Female; D005600:Fragile X Syndrome / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000187:drug effects*; D011499:Protein Processing, Post-Translational; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism
chemical_list: D001572:Benzofurans; D027682:Cation Transport Proteins; D039561:Eukaryotic Initiation Factor-4E; D018094:Receptors, Metabotropic Glutamate; C085452:cercosporamide; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases