Excess phosphoinositide 3-kinase subunit synthesis and activity as a novel therapeutic target in fragile X syndrome.
Excess phosphoinositide 3-kinase subunit synthesis and activity as a novel therapeutic target in fragile X syndrome.
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DOI：
10.1523/jneurosci.0402-10.2010
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发表时间：
2010-08-11
期刊：
影响因子：
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通讯作者：
Bassell GJ
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文献类型：
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作者：
Gross C;Nakamoto M;Yao X;Chan CB;Yim SY;Ye K;Warren ST;Bassell GJ
脆性X综合征（Fragile X Syndrome， FXS）是一种由脆性X智力迟钝蛋白（Fragile X Mental Retardation Protein， FMRP）缺失引起的遗传性神经系统疾病，该蛋白被认为介导突触mRNA翻译的负调控。FXS动物模型的一个突出特点是通过1组代谢性谷氨酸受体（gp1 mGluRs）信号被夸大，治疗FXS的治疗策略主要针对gp1 mGluRs。然而，最近的研究表明，多种受体介导的信号转导通路在FXS中失调，这表明FMRP作用于一个共同的下游信号分子。在这里，我们发现FMRP的缺乏导致磷酸肌肽3-激酶（PI3K）的突触活性过剩，PI3K是许多细胞表面受体的下游信号分子。在Fmr1敲除神经元中，过量的PI3K活性可以通过干扰gp1 mglur介导的信号传导而降低。值得注意的是，在缺乏gp1 mGluRs的非神经元细胞中也观察到PI3K活性增加。在这里，我们发现FMRP调节PI3K的催化亚基p110β的合成和突触定位。在野生型中，gp1 mGluR激活诱导p110β翻译、p110β蛋白表达和PI3K活性。相比之下，Fmr1敲除后，p110β蛋白合成和PI3K活性均升高，且对gp1 mGluR刺激不敏感。这表明，失调的PI3K信号可能是FXS突触损伤的基础。为了支持这一假设，我们发现PI3K拮抗剂可以挽救三种与fxs相关的表型：突触蛋白合成失调、AMPA受体内化过度和脊柱密度增加。因此，靶向过度的PI3K活性可能是FXS的有效治疗策略。
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 synaptic activity of phosphoinositide 3-kinase (PI3K), a downstream signaling molecule of many cell surface receptors. In Fmr1 knockout neurons, excess PI3K activity can be reduced by perturbation of gp1 mGluR-mediated signaling. Remarkably, increased PI3K activity was also observed in 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 knockout. 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.