Evidence for a fragile X mental retardation protein-mediated translational switch in metabotropic glutamate receptor-triggered Arc translation and long-term depression.
Evidence for a fragile X mental retardation protein-mediated translational switch in metabotropic glutamate receptor-triggered Arc translation and long-term depression.
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DOI：
10.1523/jneurosci.4650-11.2012
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发表时间：
2012-04-25
期刊：
影响因子：
--
通讯作者：
Huber KM
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文献类型：
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作者：
Niere F;Wilkerson JR;Huber KM
1组代谢性谷氨酸受体（mGluR）刺激蛋白合成和长期突触抑制（mGluR- ltd）在脆性X综合征小鼠模型Fmr1敲除（KO）小鼠中发生改变。Fmr1编码脆性X智力迟钝蛋白（FMRP），这是一种树突状RNA结合蛋白，在一定程度上起翻译抑制作用。目前尚不清楚FMRP是否以及如何急性调节LTD和/或LTD所需的新蛋白的快速合成，如活性调节的细胞骨架相关蛋白（Arc）。蛋白磷酸酶PP2A使FMRP去磷酸化，这有助于一些靶mrna的翻译激活。在这里，我们报道了PP2A和FMRP在S500处的去磷酸化是mglu诱导的大鼠和小鼠海马神经元树突状弧蛋白和LTD快速（5分钟）增加所必需的。在Fmr1 KO神经元中，基础的、树突的Arc蛋白水平和mGluR-LTD增强，但mglur触发的Arc合成不存在。慢病毒介导的野生型FMRP在Fmr1 KO神经元中的表达抑制了基础树突弧水平和mGluR-LTD，并恢复了mglur触发的弧的快速合成。FMRP （S500D）的磷酰亚胺抑制稳态树突电弧水平，但不能挽救mglu诱导的电弧合成。FMRP （S500A）的去磷胺既不抑制树突状电弧，也不支持mglu诱导的电弧合成。因此，在Fmr1 KO神经元中表达S500D-FMRP可以抑制mGluR-LTD，而S500A-FMRP则没有作用。这些数据支持磷酸化FMRP抑制Arc和LTD稳态翻译的模型。在mGluR激活PP2A后，FMRP迅速去磷酸化，这有助于Arc和mGluR- ltd的快速合成。
Group 1 metabotropic glutamate receptor (mGluR) stimulated protein synthesis and long-term synaptic depression (mGluR-LTD) are altered in the mouse model of Fragile X Syndrome, Fmr1 knockout (KO) mice. Fmr1 encodes Fragile X mental retardation protein (FMRP), a dendritic RNA binding protein that functions, in part, as a translational suppressor. It is unknown if and how FMRP acutely regulates LTD and/or the rapid synthesis of new proteins required for LTD, such as the activity-regulated cytoskeletal-associated protein (Arc). The protein phosphatase PP2A dephosphorylates FMRP which contributes to translational activation of some target mRNAs. Here we report that PP2A and dephosphorylation of FMRP at S500 are required for an mGluR-induced, rapid (5 min) increase in dendritic Arc protein and LTD in rat and mouse hippocampal neurons. In Fmr1 KO neurons, basal, dendritic Arc protein levels and mGluR-LTD are enhanced, but mGluR-triggered Arc synthesis is absent. Lentiviral-mediated expression of wildtype FMRP in Fmr1 KO neurons suppresses basal dendritic Arc levels and mGluR-LTD, and restores rapid mGluR-triggered Arc synthesis. A phosphomimic of FMRP (S500D) suppresses steady state dendritic Arc levels but does not rescue mGluR-induced Arc synthesis. A dephosphomimic of FMRP (S500A) neither suppresses dendritic Arc, nor supports mGluR-induced Arc synthesis. Accordingly, S500D-FMRP expression in Fmr1 KO neurons suppresses mGluR-LTD, whereas S500A-FMRP has no effect. These data support a model where phosphorylated FMRP functions to suppress steady state translation of Arc and LTD. Upon mGluR activation of PP2A, FMRP is rapidly dephosphorylated which contributes to rapid new synthesis of Arc and mGluR-LTD.