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
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    • "Several key proteins involved in synaptic transmission have been shown to be regulated by FMRP. Glutamate receptor subunits such as GluA1, 95 kDa postsynaptic density protein (PSD-95), and amyloid-precursor protein (APP) are all upregulated in the mouse model of Fragile X Syndrome, the Fmr1 knockout mouse (Westmark and Malter, 2007; Muddashetty et al., 2007; Bassell and Warren, 2008; De Rubeis and Bagni, 2011). In addition, Fmr1 knockout mice present lower levels of GABAergic proteins, such as glutamic acid decarboxylase (GAD), GABA transporters, and potassium channels (D'Hulst et al., 2009; Adusei et al., 2010; Gross et al., 2011). "
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    ABSTRACT: Fragile X Mental Retardation Protein (FMRP) is a RNA-binding protein that modulates protein synthesis at the synapse and its function is regulated by glutamate. The retina is the first structure that participates in vision, and uses glutamate to transduce electromagnetic signals from light to electrochemical signals to neurons. FMRP has been previously detected in the retina, but its localization has not been studied yet. In this work, our objectives were to describe the localization of FMRP in the retina, to determine whether different exposure to dark or light stimulus alters FMRP expression in the retina, and to compare the pattern in two different species, the mouse and chick. We found that both FMRP mRNA and protein are expressed in the retina. By immunohistochemistry analysis we found that both mouse and chick present similar FMRP expression localized mainly in both plexiform layers and the inner retina. It was also observed that FMRP is down-regulated by 24h dark adaptation compared to its expression in the retina of animals that were exposed to light for 1h after 24h in the dark. We conclude that FMRP is likely to participate in retinal physiology, since its expression changes with light exposure. In addition, the expression pattern and regulation by light of FMRP seems well conserved since it was similar in both mouse and chick.
    Full-text · Article · Dec 2015 · Experimental Eye Research
    • "The gene for APP is located at 21q21.3 (Goldgaber et al., 1987; Kang et al., 1987) and codes for a protein that is involved in synapse formation and neural plasticity (Priller et al., 2006; Turner et al., 2003). Westmark and Malter (2007) have demonstrated that FMRP binds to a guaninerich , G-quartet-like sequence of the coding region of APP mRNA and that APP mRNA co-immunopercipitates with FMRP in resting synaptoneurosomes. Subsequent studies have also demonstrated binding of FMRP to APP mRNA (Ascano et al., 2012; Darnell et al., 2011). "
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    ABSTRACT: Fragile X mental retardation protein (FMRP) is an RNA binding protein with 842 target mRNAs in mammalian brain. Silencing of the fragile X mental retardation 1 (FMR1) gene leads to loss of expression of FMRP and upregulated metabotropic glutamate receptor 5 (mGluR5) signaling resulting in the multiple physical and cognitive deficits associated with fragile X syndrome (FXS). Reduced FMRP expression has been identified in subjects with autism, schizophrenia, bipolar disorder, and major depression who do not carry the mutation for FMR1. Our laboratory has recently demonstrated altered expression of four downstream targets of FMRP-mGluR5 signaling in brains of subjects with autism: homer 1, amyloid beta A4 precursor protein (APP), ras-related C3 botulinum toxin substrate 1 (RAC1), and striatal-enriched protein tyrosine phosphatase (STEP). In the current study we investigated the expression of the same four proteins in lateral cerebella of subjects with schizophrenia, bipolar disorder, and major depression and in frontal cortex of subjects with schizophrenia and bipolar disorder. In frontal cortex we observed: 1) reduced expression of 120kDa form of APP in subjects with schizophrenia and bipolar disorder; 2) reduced expression of 61kDa and 33kDa forms of STEP in subjects with schizophrenia; 3) reduced expression of 88kDa form of APP in subjects with bipolar disorder; and 3) trends for reduced expression of 88kDa form of APP and homer 1 in subjects with schizophrenia and bipolar disorder, respectively. In lateral cerebella there was no group difference, however we observed increased expression of RAC1 in subjects with bipolar disorder, and trends for increased RAC1 in subjects with schizophrenia and major depression. Our results provide further evidence that proteins involved in the FMRP-mGluR5 signaling pathway are altered in schizophrenia and mood disorders. Copyright © 2015 Elsevier B.V. All rights reserved.
    No preview · Article · May 2015 · Schizophrenia Research
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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.
    Preview · Article · Nov 2014 · Cell Reports
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