Elevated glycogen synthase kinase-3 activity in Fragile X mice: key metabolic regulator with evidence for treatment potential.
Elevated glycogen synthase kinase-3 activity in Fragile X mice: key metabolic regulator with evidence for treatment potential.
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DOI：
10.1016/j.neuropharm.2008.09.017
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发表时间：
2009-02
影响因子：
4.7
通讯作者：
Bauchwitz RP
中科院分区：
文献类型：
--
作者：
Min WW;Yuskaitis CJ;Yan Q;Sikorski C;Chen S;Jope RS;Bauchwitz RP
脆性X综合征是一种最常见的遗传性智力迟钝，在了解其潜在缺陷和开发潜在治疗方法方面取得了重大进展。研究表明，FX动物模型中神经元代谢性谷氨酸受体5 （mGluR5）介导的信号传导受到影响，从而导致活动依赖性蛋白翻译和突触脊柱功能的改变。我们在这里证明了一种中枢代谢调节酶，糖原合成酶激酶-3 （GSK3）以一种形式存在，表明在FX小鼠大脑的几个区域活性升高。此外，我们发现选择性GSK3抑制剂以及锂能够恢复FX小鼠的突变表型。特别是锂，长期服用仍然有效，尽管它的效果是可逆的，即使从出生开始服用。mGluR5拮抗剂和GSK3抑制剂的联合不是可加性的。相反，我们发现mGluR5信号和GSK3激活在FX小鼠中协调升高，抑制mGluR5导致抑制GSK3。这些发现提高了GSK3是FXS病理的基础和核心组成部分的可能性，具有巨大的治疗潜力。
Significant advances have been made in understanding the underlying defects of and developing potential treatments for Fragile X syndrome (FXS), the most common heritable mental retardation. It has been shown that neuronal metabotropic glutamate receptor 5 (mGluR5)-mediated signaling is affected in FX animal models, with consequent alterations in activity-dependent protein translation and synaptic spine functionality. We demonstrate here that a central metabolic regulatory enzyme, glycogen synthase kinase-3 (GSK3) is present in a form indicating elevated activity in several regions of the FX mouse brain. Furthermore, we show that selective GSK3 inhibitors, as well as lithium, are able to revert mutant phenotypes of the FX mouse. Lithium, in particular, remained effective with chronic administration, although its effects were reversible even when given from birth. The combination of an mGluR5 antagonist and GSK3 inhibitors was not additive. Instead, it was discovered that mGluR5 signaling and GSK3 activation in the FX mouse are coordinately elevated, with inhibition of mGluR5 leading to inhibition of GSK3. These findings raise the possibility that GSK3 is a fundamental and central component of FXS pathology, with a substantial treatment potential.
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影响因子：
16.2
作者：
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通讯作者：
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DOI：
10.1097/chi.0b013e318040b25f
发表时间：
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影响因子：
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发表时间：
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影响因子：
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作者：
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通讯作者：
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作者：
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