Gross C, Nakamoto M, Yao X, Chan CB, Yim SY, Ye K et al. Excess phosphoinositide 3-kinase subunit synthesis and activity as a novel therapeutic target in fragile X syndrome. J Neurosci 30: 10624-10638. Evidence that a PI3K antagonist can rescue FXS phenotypes in Fmr1 KO mice

Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 08/2010; 30(32):10624-38. DOI: 10.1523/JNEUROSCI.0402-10.2010
Source: PubMed


Fragile X syndrome (FXS) is an inherited neurologic disease caused by loss of fragile X mental retardation protein (FMRP), which is hypothesized to mediate negative regulation of mRNA translation at synapses. A prominent feature of FXS animal models is exaggerated signaling through group 1 metabotropic glutamate receptors (gp1 mGluRs), and therapeutic strategies to treat FXS are targeted mainly at gp1 mGluRs. Recent studies, however, indicate that a variety of receptor-mediated signal transduction pathways are dysregulated in FXS, suggesting that FMRP acts on a common downstream signaling molecule. Here, we show that deficiency of FMRP results in excess activity of phosphoinositide 3-kinase (PI3K), a downstream signaling molecule of many cell surface receptors. In Fmr1 knock-out neurons, excess synaptic PI3K activity can be reduced by perturbation of gp1 mGluR-mediated signaling. Remarkably, increased PI3K activity was also observed in FMRP-deficient non-neuronal cells in the absence of gp1 mGluRs. Here, we show that FMRP regulates the synthesis and synaptic localization of p110beta, the catalytic subunit of PI3K. In wild type, gp1 mGluR activation induces p110beta translation, p110beta protein expression, and PI3K activity. In contrast, both p110beta protein synthesis and PI3K activity are elevated and insensitive to gp1 mGluR stimulation in Fmr1 knock-out. This suggests that dysregulated PI3K signaling may underlie the synaptic impairments in FXS. In support of this hypothesis, we show that PI3K antagonists rescue three FXS-associated phenotypes: dysregulated synaptic protein synthesis, excess AMPA receptor internalization, and increased spine density. Targeting excessive PI3K activity might thus be a potent therapeutic strategy for FXS.

Download full-text


Available from: Gary Bassell,
  • Source
    • "d by loss of function of the fragile X mental retardation protein ( FMRP ; Pieretti et al . , 1991 ; Verkerk et al . , 1991 ) , which acts as a translational repressor of specific mRNAs ( Corbin et al . , 1997 ; Feng et al . , 1997 ; Ascano et al . , 2012 ) . The absence of FMRP leads to an upregulation of many proteins , including PI3K and mTOR ( Gross et al . , 2010 ; Sharma et al . , 2010 ; Ascano et al . , 2012 ; Bhakar et al . , 2012 ) . FXS is the leading cause of inherited intellectual disability ; other neurologic manifestations include autism , anxiety , and ADHD ( Boyle and Kaufmann , 2010 ) . In addition , individuals with FXS frequently have sensory processing and sensory integration probl"
    [Show abstract] [Hide abstract]
    ABSTRACT: Defects in the rat sarcoma viral oncogene homolog (Ras)/extracellular-signal-regulated kinase and the phosphatidylinositol 3-kinase-mammalian target of rapamycin (mTOR) signaling pathways are responsible for several neurodevelopmental disorders. These disorders are an important cause for intellectual disability; additional manifestations include autism spectrum disorder, seizures, and brain malformations. Changes in synaptic function are thought to underlie the neurological conditions associated with these syndromes. We therefore studied morphology and in vivo synaptic transmission of the calyx of Held synapse, a relay synapse in the medial nucleus of the trapezoid body (MNTB) of the auditory brainstem, in mouse models of tuberous sclerosis complex (TSC), Fragile X syndrome (FXS), Neurofibromatosis type 1 (NF1), and Costello syndrome. Calyces from both Tsc1(+/-) and from Fmr1 knock-out (KO) mice showed increased volume and surface area compared to wild-type (WT) controls. In addition, in Fmr1 KO animals a larger fraction of calyces showed complex morphology. In MNTB principal neurons of Nf1 (+/) (-) mice the average delay between EPSPs and APs was slightly smaller compared to WT controls, which could indicate an increased excitability. Otherwise, no obvious changes in synaptic transmission, or short-term plasticity were observed during juxtacellular recordings in any of the four lines. Our results in these four mutants thus indicate that abnormalities of mTOR or Ras signaling do not necessarily result in changes in in vivo synaptic transmission.
    Frontiers in Cellular Neuroscience 07/2015; 9:234. DOI:10.3389/fncel.2015.00234 · 4.29 Impact Factor
  • Source
    • "We have previously reported that the levels of the PI3K product phosphatidylinositol-(3,4,5)-trisphosphate (PIP3) are increased at Fmr1 KO synapses (Gross et al., 2010). Here, we show that the ratio of PIP3 and the PI3K substrate phosphatidy- linositol-(4,5)-bisphosphate (PIP2) in hippocampal acidophilic lipid fractions is increased in Fmr1 KO mice. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The PI3K enhancer PIKE links PI3K catalytic subunits to group 1 metabotropic glutamate receptors (mGlu1/5) and activates PI3K signaling. The roles of PIKE in synaptic plasticity and the etiology of mental disorders are unknown. Here, we show that increased PIKE expression is a key mediator of impaired mGlu1/5-dependent neuronal plasticity in mouse and fly models of the inherited intellectual disability fragile X syndrome (FXS). Normalizing elevated PIKE protein levels in FXS mice reversed deficits in molecular and cellular plasticity and improved behavior. Notably, PIKE reduction rescued PI3K-dependent and -independent neuronal defects in FXS. We further show that PI3K signaling is increased in a fly model of FXS and that genetic reduction of the Drosophila ortholog of PIKE, CenG1A rescued excessive PI3K signaling, mushroom body defects, and impaired short-term memory in these flies. Our results demonstrate a crucial role of increased PIKE expression in exaggerated mGlu1/5 signaling causing neuronal defects in FXS. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 04/2015; 11(5). DOI:10.1016/j.celrep.2015.03.060 · 8.36 Impact Factor
  • Source
    • "ors of two signaling molecules to reduce protein synthe - sis rates in treated fibroblasts . It has been shown that genetic ablation of S6K1 can reduce protein synthesis and correct the molecular , synaptic , and behavioral phenotypes in Fmr1 KO mice [ Bhattacharya et al . , 2012 ] . Increased levels of p110β protein are seen in Fmr1 KO synapses [ Gross et al . , 2010 ] and FXS patient"
    [Show abstract] [Hide abstract]
    ABSTRACT: Fragile X Syndrome (FXS) is the most frequent cause of inherited intellectual disability and autism. It is caused by the absence of the fragile X mental retardation 1 (FMR1) gene product, FMRP, an RNA-binding protein involved in the regulation of translation of a subset of brain mRNAs. In Fmr1 knockout (KO) mice, the absence of FMRP results in elevated protein synthesis in the brain as well as increased signaling of many translational regulators. Whether protein synthesis is also dysregulated in FXS patients is not firmly established. Here, we demonstrate that fibroblasts from FXS patients have significantly elevated rates of basal protein synthesis along with increased levels of phosphorylated mechanistic target of rapamycin (p-mTOR), phosphorylated extracellular signal regulated kinase 1/2 (p-ERK 1/2) and phosphorylated p70 ribosomal S6 kinase 1 (p-S6K1). Treatment with small molecules that inhibit S6K1, and a known FMRP target, phosphoinositide 3-kinase (P13K) catalytic subunit p110β, lowered the rates of protein synthesis in both control and patient fibroblasts. Our data thus demonstrate that fibroblasts from FXS patients may be a useful in vitro model to test the efficacy and toxicity of potential therapeutics prior to clinical trials, as well as for drug screening and designing personalized treatment approaches.This article is protected by copyright. All rights reserved
    Human Mutation 12/2014; 35(12). DOI:10.1002/humu.22699 · 5.14 Impact Factor
Show more