The translation of translational control by FMRP: therapeutic targets for FXS

Abstract

De novo protein synthesis is necessary for long-lasting modifications in synaptic strength and dendritic spine dynamics that underlie cognition. Fragile X syndrome (FXS), characterized by intellectual disability and autistic behaviors, holds promise for revealing the molecular basis for these long-term changes in neuronal function. Loss of function of the fragile X mental retardation protein (FMRP) results in defects in synaptic plasticity and cognition in many models of the disease. FMRP is a polyribosome-associated RNA-binding protein that regulates the synthesis of a set of plasticity-reated proteins by stalling ribosomal translocation on target mRNAs. The recent identification of mRNA targets of FMRP and its upstream regulators, and the use of small molecules to stall ribosomes in the absence of FMRP, have the potential to be translated into new therapeutic avenues for the treatment of FXS.

Figure 1. FMRP and small molecules act to stall ribosomal elongation

Upper panel, active translation: mRNAs are translated into protein by translocating ribosomes (40S and 60S subunits are shown in light blue) that assemble at the start codon (AUG) and dissociate at the stop codon (for example, UAG). Middle panel, FMRP-repressed translation: FMRP inhibits ribosomal translocation on specific mRNAs in a complex consisting of target mRNA and several stacked or condensed ribosomes. As the stoichiometry of FMRP to ribosomes to target mRNAs is not known, a minimum of one FMRP molecule (red sphere) is depicted in the stalled complex, recognizing the possibility that additional FMRP molecules (illustrated by transparent red spheres) may exist in the stalled complex. Lower panel, minocycline-repressed translation: Minocycline, a tetracycline analog, (orange spheres) and many other small molecules inhibit translation by interfering with ribosomal translocation in different ways. Because of the similarity in proposed action between FMRP and such small molecules it is possible that they might partially replace FMRP functions lost in fragile X syndrome and be therapeutically beneficial.

Figure 2. Signaling Pathways Controlling Translation in Normal and FXS Model Mice

A) Translational control in neurons of normal mice. Metabotropic glutamate receptor 5 (mGluR5) and NMDA receptors are coupled to PI3K/Akt/mTORC1 and MEK/ERK signaling to regulate cap-dependent translation (for detailed reviews see^–,–). Blue colored proteins are those whose mRNAs are FMRP targets. B) Translational control in neurons of FXS model mice that lack FMRP. Green arrows indicate either total or phosphorylated levels (indicated by red P) of proteins that have been reported to increase in either FXS model mice or cells from FXS individuals^,,,,,,,. Proteins with red lines around them indicate those that have been successfully targeted either pharmacologically or genetically to reverse molecular, morphological, synaptic, and/or behavioral phenotypes in cellular and/or animal models of FXS^–,,,,,,,,.

Figure 2. Signaling Pathways Controlling Translation in Normal and FXS Model Mice

A) Translational control in neurons of normal mice. Metabotropic glutamate receptor 5 (mGluR5) and NMDA receptors are coupled to PI3K/Akt/mTORC1 and MEK/ERK signaling to regulate cap-dependent translation (for detailed reviews see^–,–). Blue colored proteins are those whose mRNAs are FMRP targets. B) Translational control in neurons of FXS model mice that lack FMRP. Green arrows indicate either total or phosphorylated levels (indicated by red P) of proteins that have been reported to increase in either FXS model mice or cells from FXS individuals^,,,,,,,. Proteins with red lines around them indicate those that have been successfully targeted either pharmacologically or genetically to reverse molecular, morphological, synaptic, and/or behavioral phenotypes in cellular and/or animal models of FXS^–,,,,,,,,.