FMRP Mediates mGluR5-Dependent Translation of Amyloid Precursor Protein

Department of Pathology and Laboratory Medicine, Waisman Center for Developmental Disabilities, University of Wisconsin, Madison, Wisconsin, United States of America.
PLoS Biology (Impact Factor: 9.34). 04/2007; 5(3):e52. DOI: 10.1371/journal.pbio.0050052
Source: PubMed


Author Summary

Alzheimer disease (AD) and fragile X syndrome (FXS) are devastating neurological disorders associated with synaptic dysfunction resulting in cognitive impairment and behavioral deficits. Despite these similar endpoints, the pathobiology of AD and FXS have not previously been linked. We have established that translation of amyloid precursor protein (APP), which is cleaved to generate neurotoxic βamyloid, is normally repressed by the fragile X mental retardation protein (FMRP) in the dendritic processes of neurons. Activation of a particular subtype of glutamate receptor (mGluR5) rapidly increases translation of APP in neurons by displacing FMRP from a guanidine-rich sequence in the coding region of APP mRNA. In the absence of FMRP, APP synthesis is constitutively increased and nonresponsive to mGluR-mediated signaling. Excess APP is proteolytically cleaved to generate significantly elevated βamyloid in multiple mutant mouse strains lacking FMRP compared to wild type. Our data support a growing consensus that FMRP binds to guanine-rich domains of some dendritic mRNAs, suppressing their translation and suggest that AD (neurodegenerative disorder) and FXS (neurodevelopmental disorder) may share a common molecular pathway leading to the overproduction of APP and its protein-cleaving derivatives.

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Available from: James S Malter, Oct 01, 2015
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    • "The motifs recognized by FMRP have been extensively characterized (Ascano et al., 2012; Brown et al., 2001; Chen et al., 2003; Darnell et al., 2001) and include both G-rich sequences and G-quadruplexes (GQs) (Muddashetty et al., 2011; Phan et al., 2011; Westmark and Malter, 2007). GQs are stable nucleic acid structures that can be substrates for helicases, as is the case for the primarily nuclear helicases G4R1/RHAU and DHX9 (Chakraborty and Grosse, 2011; Creacy et al., 2008). "
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    ABSTRACT: The fragile X mental retardation protein FMRP regulates translation of its bound mRNAs through incompletely defined mechanisms. FMRP has been linked to the microRNA pathway, and we show here that it associates with the RNA helicase MOV10, also associated with the microRNA pathway. FMRP associates with MOV10 directly and in an RNA-dependent manner and facilitates MOV10's association with RNAs in brain and cells, suggesting a cooperative interaction. We identified the RNAs recognized by MOV10 using RNA immunoprecipitation and iCLIP. Examination of the fate of MOV10 on RNAs revealed a dual function for MOV10 in regulating translation: it facilitates microRNA-mediated translation of some RNAs, but it also increases expression of other RNAs by preventing AGO2 function. The latter subset was also bound by FMRP in close proximity to the MOV10 binding site, suggesting that FMRP prevents MOV10-mediated microRNA suppression. We have identified a mechanism for FMRP-mediated translational regulation through its association with MOV10. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 11/2014; 9(5). DOI:10.1016/j.celrep.2014.10.054 · 8.36 Impact Factor
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    • "It is now well recognized that mGluR5 regulates the activity of the fragile X mental retardation protein (FMRP), a RNA binding protein that functions to repress protein synthesis at synapses [21-25]. The activation of mGluR5 results in FMRP-dependent increases in both APP and FMRP expression [16,26]. This increase in APP expression results in the augmented secretion of both toxic Aβ42 oligomers and the non-toxic soluble APP (sAPPα) fragment [16,24]. "
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    ABSTRACT: Background Alzheimer’s disease (AD) pathology occurs in part as the result of excessive production of β-amyloid (Aβ). Metabotropic glutamate receptor 5 (mGluR5) is now considered a receptor for Aβ and consequently contributes to pathogenic Aβ signaling in AD. Results Genetic deletion of mGluR5 rescues the spatial learning deficits observed in APPswe/PS1ΔE9 AD mice. Moreover, both Aβ oligomer formation and Aβ plaque number are reduced in APPswe/PS1ΔE9 mice lacking mGluR5 expression. In addition to the observed increase in Aβ oligomers and plaques in APPswe/PS1ΔE9 mice, we found that both mTOR phosphorylation and fragile X mental retardation protein (FMRP) expression were increased in these mice. Genetic deletion of mGluR5 reduced Aβ oligomers, plaques, mTOR phosphorylation and FMRP expression in APPswe/PS1ΔE9 mice. Conclusions Thus, we propose that Aβ activation of mGluR5 appears to initiate a positive feedback loop resulting in increased Aβ formation and AD pathology in APPswe/PS1ΔE9 mice via mechanism that is regulated by FMRP.
    Molecular Brain 05/2014; 7(1):40. DOI:10.1186/1756-6606-7-40 · 4.90 Impact Factor
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    • "To date, however, interactions between these regulatory mechanisms on APP expression have not been evidenced. The Fragile X Mental Retardation Protein (FMRP) binds APP mRNA and represses its translation (Westmark and Malter, 2007). Interestingly RanBP9 may interact with FMRP and inhibit its RNA binding activity (Menon et al., 2004). "
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    ABSTRACT: Neurodegeneration associated with amyloid β (Aβ) peptide accumulation, synaptic loss, and memory impairment are pathophysiological features of Alzheimer's disease (AD). Numerous microRNAs regulate amyloid precursor protein (APP) expression and metabolism. We previously reported that miR-101 is a negative regulator of APP expression in cultured hippocampal neurons. In this study, a search for predicted APP metabolism-associated miR-101 targets led to the identification of a conserved miR-101 binding site within the 3' untranslated region (UTR) of the mRNA encoding Ran-binding protein 9 (RanBP9). RanBP9 increases APP processing by β-amyloid converting enzyme 1 (BACE1), secretion of soluble APPβ (sAPPβ), and generation of Aβ. MiR-101 significantly reduced reporter gene expression when co-transfected with a RanBP9 3'-UTR reporter construct, while site-directed mutagenesis of the predicted miR-101 target site eliminated the reporter response. To investigate the effect of stable inhibition of miR-101 both in vitro and in vivo, a microRNA sponge was developed to bind miR-101 and derepress its targets. Four tandem bulged miR-101 responsive elements (REs), located downstream of the enhanced green fluorescence protein (EGFP) open reading frame and driven by the synapsin promoter, were placed in a lentiviral vector to create the pLSyn-miR-101 sponge. Delivery of the sponge to primary hippocampal neurons significantly increased both APP and RanBP9 expression, as well as sAPPβ levels in the conditioned medium. Importantly, silencing of endogenous RanBP9 reduced sAPPβ levels in miR-101 sponge-containing hippocampal cultures, indicating that miR-101 inhibition may increase amyloidogenic processing of APP by RanBP9. Lastly, the impact of miR-101 on its targets was demonstrated in vivo by intrahippocampal injection of the pLSyn-miR-101 sponge into C57BL6 mice. This study thus provides the basis for studying the consequences of long-term miR-101 inhibition on the pathology of AD.
    Frontiers in Cellular Neuroscience 02/2014; 8:37. DOI:10.3389/fncel.2014.00037 · 4.29 Impact Factor
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