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Featured ArticleArticles, Neurobiology of Disease

Excess Phosphoinositide 3-Kinase Subunit Synthesis and Activity as a Novel Therapeutic Target in Fragile X Syndrome

Christina Gross, Mika Nakamoto, Xiaodi Yao, Chi-Bun Chan, So Y. Yim, Keqiang Ye, Stephen T. Warren and Gary J. Bassell
Journal of Neuroscience 11 August 2010, 30 (32) 10624-10638; DOI: https://doi.org/10.1523/JNEUROSCI.0402-10.2010
Christina Gross
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Mika Nakamoto
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Xiaodi Yao
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Chi-Bun Chan
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So Y. Yim
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Keqiang Ye
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Stephen T. Warren
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Gary J. Bassell
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Abstract

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 p110β, the catalytic subunit of PI3K. In wild type, gp1 mGluR activation induces p110β translation, p110β protein expression, and PI3K activity. In contrast, both p110β 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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The Journal of Neuroscience: 30 (32)
Journal of Neuroscience
Vol. 30, Issue 32
11 Aug 2010
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Excess Phosphoinositide 3-Kinase Subunit Synthesis and Activity as a Novel Therapeutic Target in Fragile X Syndrome
Christina Gross, Mika Nakamoto, Xiaodi Yao, Chi-Bun Chan, So Y. Yim, Keqiang Ye, Stephen T. Warren, Gary J. Bassell
Journal of Neuroscience 11 August 2010, 30 (32) 10624-10638; DOI: 10.1523/JNEUROSCI.0402-10.2010

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Excess Phosphoinositide 3-Kinase Subunit Synthesis and Activity as a Novel Therapeutic Target in Fragile X Syndrome
Christina Gross, Mika Nakamoto, Xiaodi Yao, Chi-Bun Chan, So Y. Yim, Keqiang Ye, Stephen T. Warren, Gary J. Bassell
Journal of Neuroscience 11 August 2010, 30 (32) 10624-10638; DOI: 10.1523/JNEUROSCI.0402-10.2010
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