A new function for the fragile X mental retardation protein in regulation of PSD-95 mRNA stability

Zalfa, Francesca; Eleuteri, Boris; Dickson, Kirsten S.; Mercaldo, Valentina; Rubeis, Silvia De; Penta, Alessandra di; Tabolacci, Elisabetta; Chiurazzi, Pietro; Neri, Giovanni; Grant, Seth G. N.; Bagni, Claudia

doi:10.1038/nn1893

Cited by 320 publications

(326 citation statements)

References 51 publications

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“…FMRP is an mRNA-binding protein that plays a role in various aspects of activity-dependent mRNA metabolism in neurons, such as mRNA transport (Dictenberg et al, 2008;Estes et al, 2008), stability (Zalfa et al, 2007), and regulation of mRNA translation (see, eg, Zalfa et al, 2003;Muddashetty et al, 2007;Bechara et al, 2009). Here, we will focus on the role of FMRP in translational control, as this is the so far best-studied function of FMRP in RNA metabolism.…”

Section: Fmrp: a Key Regulator Of Neuronal Functionmentioning

confidence: 99%

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Groß

Berry‐Kravis

Bassell

2011

Neuropsychopharmacol

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Fragile X syndrome (FXS) is an inherited neurodevelopmental disease caused by loss of function of the fragile X mental retardation protein (FMRP). In the absence of FMRP, signaling through group 1 metabotropic glutamate receptors is elevated and insensitive to stimulation, which may underlie many of the neurological and neuropsychiatric features of FXS. Treatment of FXS animal models with negative allosteric modulators of these receptors and preliminary clinical trials in human patients support the hypothesis that metabotropic glutamate receptor signaling is a valuable therapeutic target in FXS. However, recent research has also shown that FMRP may regulate diverse aspects of neuronal signaling downstream of several cell surface receptors, suggesting a possible new route to more direct disease-targeted therapies. Here, we summarize promising recent advances in basic research identifying and testing novel therapeutic strategies in FXS models, and evaluate their potential therapeutic benefits. We provide an overview of recent and ongoing clinical trials motivated by some of these findings, and discuss the challenges for both basic science and clinical applications in the continued development of effective disease mechanism-targeted therapies for FXS.

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Section: Fmrp: a Key Regulator Of Neuronal Functionmentioning

confidence: 99%

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Groß

Berry‐Kravis

Bassell

2011

Neuropsychopharmacol

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“…Additionally, FMRP may have a role in stabilizing mRNA transcripts. In mice, FMRP binds the transcript encoding PSD-95, an adaptor protein that regulates synaptic signalling and has a role in learning and cortical plasticity (Zalfa et al, 2007). This interaction occurs through the 3' untranslated region of the PSD-95 mRNA, increasing its stability.…”

Section: Sema3fmentioning

confidence: 99%

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

et al. 2010

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The purpose of this study was to examine the expression of GABAergic proteins in Fmr1 knockout mice during brain maturation and to assess behavioural changes potentially linked to perturbations in the GABAergic system. Quantitative western blotting of the forebrain revealed that compared to wild-type mice, the GABA A receptor α1, β2, and δ subunits, and the GABA catabolic enzymes GABA transaminase and SSADH were down-regulated during postnatal development, while GAD65 was up-regulated in the adult knockout mouse forebrain. In tests of locomotor activity, the suppressive effect on motor activity of the GABA A β2/3 subunit-selective drug loreclezole was impaired in the mutant mice. In addition, sleep time induced by the GABA A β2/3-selective anaesthetic drug etomidate was decreased in the knockout mice. Our results indicate that disruptions in the GABAergic system in the developing brain may result in behavioural consequences in adults with fragile X syndrome.iii

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“…FMRP is an RNA binding protein that associates with polyribosomes and is localized in neurons in the form of granules that move in a microtubule dependent manner with the speed of RNA transport (Antar et al, 2005;De Diego Otero et al, 2002;Wang et al, 2007). Moreover, FMRP has been shown to influence the translation efficacy of several of its target mRNAs (reviewed in (Bagni and Greenough, 2005;Bardoni et al, 2006;Zalfa et al, 2007), which also implicates local translation at synaptic sites (Greenough et al, 2001;Muddashetty et al, 2007;Weiler et al, 1997;Weiler et al, 2004). In most cases, FMRP acts as a translational repressor (Laggerbauer et al, 2001;Lu et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Rescue of behavioral phenotype and neuronal protrusion morphology in Fmr1 KO mice

Vrij

Levenga

Linde

et al. 2008

Neurobiology of Disease

296

250

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Lack of fragile X mental retardation protein (FMRP) causes Fragile X Syndrome, the most common form of inherited mental retardation. FMRP is an RNA-binding protein and is a component of messenger ribonucleoprotein complexes, associated with brain polyribosomes, including dendritic polysomes. FMRP is therefore thought to be involved in translational control of specific mRNAs at synaptic sites. In mice lacking FMRP, protein synthesis-dependent synaptic plasticity is altered and structural malformations of dendritic protrusions occur. One hypothesized cause of the disease mechanism is based on exaggerated group I mGluR receptor activation. In this study, we examined the effect of the mGluR5 antagonist MPEP on Fragile X related behavior in Fmr1 KO mice. Our results demonstrate a clear defect in prepulse inhibition of startle in Fmr1 KO mice, that could be rescued by MPEP. Moreover, we show for the first time a structural rescue of Fragile X related protrusion morphology with two independent mGluR5 antagonists.

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A new function for the fragile X mental retardation protein in regulation of PSD-95 mRNA stability

Cited by 320 publications

References 51 publications

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

Rescue of behavioral phenotype and neuronal protrusion morphology in Fmr1 KO mice

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