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

• Authors: Anwesha Banerjee, Emory University; Marius Ifrim, Emory University; Arielle N. Valdez, Emory University; Nisha Raj, Emory University; Gary Bassell, Emory University
• Journal Title: Brain Research
• Volume: Volume 1693, Number Pt A
• Publisher: Elsevier Science B.V. | 2018-08-15, Pages 24-36
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1016/j.brainres.2018.04.008
• Subjects: Biology, Neuroscience; Biology, Cell; Health Sciences, Rehabilitation and Therapy
• Keywords: Science & Technology; Life Sciences & Biomedicine; Neurosciences; Neurosciences & Neurology; Fragile X syndrome; mRNA translation; mRNA localization; RNA binding protein; Dendritic spine; iPSC; Mental retardation protein; Embryonic stem cells; Glutamate transporter GLT1; G-quadruplex structures; Messenger RNA; Mouse model; Dendritic spine; RGG box; Dependent translation; Synaptic plasticity

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.