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.

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    • "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"
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    • "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. "
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    • "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"
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