Aberrant RNA translation in fragile X syndrome: From FMRP mechanisms to emerging therapeutic strategies

Abstract

Research in the past decades has unfolded the multifaceted role of Fragile X mental retardation protein (FMRP) and how its absence contributes to the pathophysiology of Fragile X syndrome (FXS). Excess signaling through group 1 metabotropic glutamate receptors is commonly observed in mouse models of FXS, which in part is attributed to dysregulated translation and downstream signaling. Considering the wide spectrum of cellular and physiologic functions that loss of FMRP can affect in general, it may be advantageous to pursue disease mechanism based treatments that directly target translational components or signaling factors that regulate protein synthesis. Various FMRP targets upstream and downstream of the translational machinery are therefore being investigated to further our understanding of the molecular mechanism of RNA and protein synthesis dysregulation in FXS as well as test their potential role as therapeutic interventions to alleviate FXS associated symptoms. In this review, we will broadly discuss recent advancements made towards understanding the role of FMRP in translation regulation, new pre-clinical animal models with FMRP targets located at different levels of the translational and signal transduction pathways for therapeutic intervention as well as future use of stem cells to model FXS associated phenotypes.

Keywords: Dendritic spine; Fragile X syndrome; RNA binding protein; iPSC; mRNA localization; mRNA translation.

Fig. 1.

The schematic depicts multiple mechanisms by which FMRP regulates translation. (1) Phosphorylated-FMRP regulates translation of target mRNAs by directly associating with polyribosomes and mRNP complexes. FMRP associates with other RNA binding proteins such as MOV10 (RNA Helicase) and ZC3H14 to regulate translation. (2) FMRP can regulate mGlu5 mediated translation by dephosphorylation of FMRP, ubiquitination of FMRP and release of RISC complex. (3) Beta-catenin, a component of Fragile X granule, regulates the distribution of the pool of presynaptic vesicles and regulates plasticity. For the purpose of simplicity, this schematic does not represent the exhaustive list of FMRP targets that has been discussed in the review.