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.

Mechanisms underlying auditory processing deficits in Fragile X syndrome

“…FMRP regulates many aspects of RNA biology from RNA transport, stability, to mRNA translation . The best‐described biological role of FMRP in neurons is to bind a subset of mRNAs and to suppress their translation . Appropriate stimulation of neurons can reverse this suppression, most likely by altering the phosphorylation state of FMRP, leading to increased synthesis of the protein products of these mRNAs.…”

“…12,13 The best-described biological role of FMRP in neurons is to bind a subset of mRNAs and to suppress their translation. 14,15 Appropriate stimulation of neurons can reverse this suppression, most likely by altering the phosphorylation state of FMRP, leading to increased synthesis of the protein products Abbreviations: ASD, autism spectrum disorder; AGS, audiogenic seizures; ASR, acoustic startle response; E/I, ratio of excitation to inhibition; EPSC, excitatory postsynaptic current; IPSC, inhibitory postsynaptic current; Fmr1, non-human mammalian fragile X mental retardation 1 gene; FMR1, human fragile X mental retardation 1 gene; FMRP, Fragile X mental retardation protein; FXS, Fragile X syndrome; GlyT2, glycine transporter 2; ITD, interaural time difference; IID/ILD, interaural intensity/level difference; IPL, interpeak latency; LNTB, lateral nucleus of the trapezoid body; LSO, lateral superior olive; mGluR, metabotropic glutamate receptor; MMP, matrix metalloprotease; MNTB, medial nucleus of the trapezoid body; MSO, medial superior olive; NL, nucleus laminaris; NM, nucleus magnocellularis; PNN, perineuronal nets; PPI, prepulse inhibition; PV, parvalbumin; SON, superior olivary nucleus; VCN, ventral cochlear nucleus; VGAT, vesicular GABA transporter; VGLUT, vesicular glutamate transporter; VNTB, ventral nucleus of the trapezoid body. of these mRNAs. There are on the order of ~1000 mRNAs that bind FMRP and these are termed targets of FMRP.…”

Single Cell Transcriptomics Reveals Dysregulated Cellular and Molecular Networks in a Fragile X Syndrome model

“…The top downregulated genes related to synapses and neuronal projections ( Figure 4c) include Vamp2, a key component of synaptic vesicle trafficking 68 ; Camkk2 and Camk2b, which are both involved in the formation of dendritic spines 69 ; and Grm5, which encodes for the mGluR5 receptor, and noticeably is one of the main proposed therapeutic targets for FXS 70 . Reduced abundance of these and other synaptic and neuronal projection related mRNAs reveals multi-leveled transcriptome deficits (vesicle transport, cell morphology and receptors, affecting both pre and postsynaptic structures), which could be behind the known deficits of FXS neurites and synaptic development 4 .…”

Dysregulated Translation in Neurodevelopmental Disorders: An Overview of Autism‐Risk Genes Involved in Translation

“…Nevertheless, the molecular mechanism of how FMRP stops ribosome translocation on mRNA is not clear. For more insights on FMRP and FXS, please refer to the previous reviews (De Rubeis et al, 2012;Santoro et al, 2012;Pasciuto and Bagni, 2014;Banerjee et al, 2018).…”