scholarly journals FMRP inhibits translation elongation independent of mRNA G-quadruplexes

2022 ◽  
Author(s):  
MaKenzie R. Scarpitti ◽  
Julia E. Warrick ◽  
Michael G. Kearse
Keyword(s):  
Rna Binding ◽  
Fragile X ◽  
Mrna Localization ◽  
Autism Spectrum ◽  
Rna Sequences ◽  
Translation Elongation ◽  
Mental Retardation Protein ◽  
Work Shifts ◽  
Spectrum Disorders ◽  
Reporter Mrna

Loss of functional fragile X mental retardation protein (FMRP) causes fragile X syndrome, the leading form of inherited intellectual disability and the most common monogenic cause of autism spectrum disorders. FMRP is an RNA-binding protein that controls neuronal mRNA localization and translation. Notably, FMRP is thought to inhibit translation elongation after being recruited to target transcripts via binding RNA G-quadruplexes (G4s) within the coding sequence. Here we directly tested this model and report that FMRP inhibits translation elongation independent of mRNA G4s. Furthermore, we found that the RGG box motif together with its natural C-terminal domain forms a non-canonical RNA-binding domain (ncRBD) that binds reporter mRNA and all four polymeric RNA sequences. The ncRBD is essential for FMRP to inhibit translation. Transcripts that are bound by FMRP through the ncRBD co-sediment with heavy polysomes, which is consistent with stalling elongating ribosomes and a subsequent accumulation of slowed polysomes. Together, this work shifts our understanding of how FMRP inhibits translation elongation and supports a model where repression is driven by local FMRP and mRNA concentrations rather than target mRNA sequence.

scholarly journals Dicer-Derived MicroRNAs Are Utilized by the Fragile X Mental Retardation Protein for Assembly on Target RNAs

2006 ◽  
Vol 2006 ◽  
pp. 1-12 ◽  
Author(s):  
Isabelle Plante ◽  
Laetitia Davidovic ◽  
Dominique L. Ouellet ◽  
Lise-Andrée Gobeil ◽  
Sandra Tremblay ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Translational Control ◽  
Mammalian Cells ◽  
Rna Binding ◽  
Fragile X ◽  
Rna Sequences ◽  
Fragile X Mental Retardation ◽  
Mental Retardation Protein ◽  
Rnp Complex

In mammalian cells, fragile X mental retardation protein (FMRP) has been reported to be part of a microRNA (miRNA)-containing effector ribonucleoprotien (RNP) complex believed to mediate translational control of specific mRNAs. Here, using recombinant proteins, we demonstrate that human FMRP can act as a miRNA acceptor protein for the ribonuclease Dicer and facilitate the assembly of miRNAs on specific target RNA sequences. The miRNA assembler property of FMRP was abrogated upon deletion of its single-stranded (ss) RNA binding K-homology domains. The requirement of FMRP for efficient RNA interference (RNAi) in vivo was unveiled by reporter gene silencing assays using various small RNA inducers, which also supports its involvement in an ss small interfering RNA (siRNA)-containing RNP (siRNP) effector complex in mammalian cells. Our results define a possible role for FMRP in RNA silencing and may provide further insight into the molecular defects in patients with the fragile X syndrome.

scholarly journals The RNA-binding fragile-X mental retardation protein and its role beyond the brain

2020 ◽  
Vol 12 (4) ◽  
pp. 903-916 ◽  
Author(s):  
Cassandra Malecki ◽  
Brett D. Hambly ◽  
Richmond W. Jeremy ◽  
Elizabeth N. Robertson
Keyword(s):  
Mental Retardation ◽  
Rna Binding ◽  
Fragile X ◽  
Fragile X Mental Retardation ◽  
Mental Retardation Protein ◽  
The Brain

scholarly journals Identification of FMRP target mRNAs in the developmental brain: FMRP might coordinate Ras/MAPK, Wnt/β-catenin, and mTOR signaling during corticogenesis

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Cristine R. Casingal ◽  
Takako Kikkawa ◽  
Hitoshi Inada ◽  
Yukio Sasaki ◽  
Noriko Osumi
Keyword(s):  
Brain Development ◽  
Rna Binding ◽  
Fragile X ◽  
Autism Spectrum ◽  
Mtor Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Sequencing Analysis ◽  
Embryonic Brain ◽  
Target Mrnas ◽  
Mrna Targets

AbstractCorticogenesis is one of the most critical and complicated processes during embryonic brain development. Any slight impairment in corticogenesis could cause neurodevelopmental disorders such as Fragile X syndrome (FXS), of which symptoms contain intellectual disability (ID) and autism spectrum disorder (ASD). Fragile X mental retardation protein (FMRP), an RNA-binding protein responsible for FXS, shows strong expression in neural stem/precursor cells (NPCs) during corticogenesis, although its function during brain development remains largely unknown. In this study, we attempted to identify the FMRP target mRNAs in the cortical primordium using RNA immunoprecipitation sequencing analysis in the mouse embryonic brain. We identified 865 candidate genes as targets of FMRP involving 126 and 118 genes overlapped with ID and ASD-associated genes, respectively. These overlapped genes were enriched with those related to chromatin/chromosome organization and histone modifications, suggesting the involvement of FMRP in epigenetic regulation. We further identified a common set of 17 FMRP “core” target genes involved in neurogenesis/FXS/ID/ASD, containing factors associated with Ras/mitogen-activated protein kinase, Wnt/β-catenin, and mammalian target of rapamycin (mTOR) pathways. We indeed showed overactivation of mTOR signaling via an increase in mTOR phosphorylation in the Fmr1 knockout (Fmr1 KO) neocortex. Our results provide further insight into the critical roles of FMRP in the developing brain, where dysfunction of FMRP may influence the regulation of its mRNA targets affecting signaling pathways and epigenetic modifications.

scholarly journals Compromising the phosphodependent regulation of the GABAAR β3 subunit reproduces the core phenotypes of autism spectrum disorders

2015 ◽  
Vol 112 (48) ◽  
pp. 14805-14810 ◽  
Author(s):  
Thuy N. Vien ◽  
Amit Modgil ◽  
Armen M. Abramian ◽  
Rachel Jurd ◽  
Joshua Walker ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Fragile X ◽  
Repetitive Behavior ◽  
Autism Spectrum ◽  
Membrane Stability ◽  
Receptor Subtypes ◽  
Neuronal Inhibition ◽  
Spectrum Disorders ◽  
Spine Structure

Alterations in the efficacy of neuronal inhibition mediated by GABAA receptors (GABAARs) containing β3 subunits are continually implicated in autism spectrum disorders (ASDs). In vitro, the plasma membrane stability of GABAARs is potentiated via phosphorylation of serine residues 408 and 409 (S408/9) in the β3 subunit, an effect that is mimicked by their mutation to alanines. To assess if modifications in β3 subunit expression contribute to ASDs, we have created a mouse in which S408/9 have been mutated to alanines (S408/9A). S408/9A homozygotes exhibited increased phasic, but decreased tonic, inhibition, events that correlated with alterations in the membrane stability and synaptic accumulation of the receptor subtypes that mediate these distinct forms of inhibition. S408/9A mice exhibited alterations in dendritic spine structure, increased repetitive behavior, and decreased social interaction, hallmarks of ASDs. ASDs are frequently comorbid with epilepsy, and consistent with this comorbidity, S408/9A mice exhibited a marked increase in sensitivity to seizures induced by the convulsant kainic acid. To assess the relevance of our studies using S408/9A mice for the pathophysiology of ASDs, we measured S408/9 phosphorylation in Fmr1 KO mice, a model of fragile X syndrome, the most common monogenetic cause of ASDs. Phosphorylation of S408/9 was selectively and significantly enhanced in Fmr1 KO mice. Collectively, our results suggest that alterations in phosphorylation and/or activity of β3-containing GABAARs may directly contribute to the pathophysiology of ASDs.

scholarly journals Kinase pathway inhibition restores PSD95 induction in neurons lacking fragile X mental retardation protein

2019 ◽  
pp. 201812056
Author(s):  
Ying Yang ◽  
Yang Geng ◽  
Dongyun Jiang ◽  
Lin Ning ◽  
Hyung Joon Kim ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Mental Retardation ◽  
Rna Binding ◽  
Fragile X ◽  
Alternative Pathways ◽  
Fragile X Mental Retardation ◽  
Mrna Targets ◽  
Mental Retardation Protein ◽  
Pathway Inhibition

Fragile X syndrome (FXS) is the leading monogenic cause of autism and intellectual disability. FXS is caused by loss of expression of fragile X mental retardation protein (FMRP), an RNA-binding protein that regulates translation of numerous mRNA targets, some of which are present at synapses. While protein synthesis deficits have long been postulated as an etiology of FXS, how FMRP loss affects distributions of newly synthesized proteins is unknown. Here we investigated the role of FMRP in regulating expression of new copies of the synaptic protein PSD95 in an in vitro model of synaptic plasticity. We find that local BDNF application promotes persistent accumulation of new PSD95 at stimulated synapses and dendrites of cultured neurons, and that this accumulation is absent in FMRP-deficient mouse neurons. New PSD95 accumulation at sites of BDNF stimulation does not require known mechanisms regulating FMRP–mRNA interactions but instead requires the PI3K-mTORC1-S6K1 pathway. Surprisingly, in FMRP-deficient neurons, BDNF induction of new PSD95 accumulation can be restored by mTORC1-S6K1 blockade, suggesting that constitutively high mTORC1-S6K1 activity occludes PSD95 regulation by BDNF and that alternative pathways exist to mediate induction when mTORC1-S6K1 is inhibited. This study provides direct evidence for deficits in local protein synthesis and accumulation of newly synthesized protein in response to local stimulation in FXS, and supports mTORC1-S6K1 pathway inhibition as a potential therapeutic approach for FXS.

Parental reports on early language and motor milestones in fragile X syndrome with and without autism spectrum disorders

2012 ◽  
Vol 16 (1) ◽  
pp. 58-66 ◽  
Author(s):  
Rebecca Hinton ◽  
Dejan B. Budimirovic ◽  
Peter B. Marschik ◽  
Victor B. Talisa ◽  
Christa Einspieler ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Autism Spectrum ◽  
Early Language ◽  
Parental Reports ◽  
Spectrum Disorders

scholarly journals Fragile phagocytes: FMRP positively regulates engulfment activity

2017 ◽  
Vol 216 (3) ◽  
pp. 531-533 ◽  
Author(s):  
Mary A. Logan
Keyword(s):  
Innate Immunity ◽  
Drosophila Melanogaster ◽  
Immune System ◽  
Immune Cells ◽  
Fragile X ◽  
Autism Spectrum ◽  
Abnormal Development ◽  
System Function ◽  
Immune System Function ◽  
Spectrum Disorders

Defective immune system function is implicated in autism spectrum disorders, including Fragile X syndrome. In this issue, O’Connor et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201607093) demonstrate that phagocytic activity of systemic immune cells is compromised in a Drosophila melanogaster model of Fragile X, highlighting intriguing new mechanistic connections between FMRP, innate immunity, and abnormal development.

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