Fragile X mental retardation protein induces synapse loss through acute postsynaptic translational regulation
Fragile X mental retardation protein induces synapse loss through acute postsynaptic translational regulation
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DOI：
10.1523/jneurosci.0054-07.2007
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发表时间：
2007-03-21
影响因子：
5.3
通讯作者：
Huber, Kimberly M.
中科院分区：
文献类型：
--
作者：
Pfeiffer, Brad E.;Huber, Kimberly M.
脆性X综合征，以及其他形式的智力迟钝和自闭症，与树突棘数量和结构的改变有关。脆性X综合征是由脆性X智力低下蛋白（FMRP）的功能缺失突变引起的，FMRP是一种调节体内蛋白质合成的RNA结合蛋白。目前还不清楚FMRP是否在突触数量、功能或成熟的调节中起直接的、细胞自主的作用。在这里，我们报告说，急性突触后表达FMRP在Fmr1敲除（KO）神经元的功能和结构突触的数量减少的结果，而不影响其突触强度或成熟状态。类似地，内源性表达FMRP（野生型）的神经元比邻近的Fmr1 KO神经元具有更少的突触。完整的K同源结构域2（KH 2）RNA结合结构域和FMRP在S500的去磷酸化是FMRP对突触数量的影响所必需的，表明FMRP与RNA和翻译多聚核糖体的相互作用导致突触丢失。
Fragile X syndrome, as well as other forms of mental retardation and autism, is associated with altered dendritic spine number and structure. Fragile X syndrome is caused by loss-of-function mutations in Fragile X mental retardation protein (FMRP), an RNA-binding protein that regulates protein synthesis in vivo. It is unknown whether FMRP plays a direct, cell-autonomous role in regulation of synapse number, function, or maturation. Here, we report that acute postsynaptic expression of FMRP in Fmr1 knock-out (KO) neurons results in a decrease in the number of functional and structural synapses without an effect on their synaptic strength or maturational state. Similarly, neurons endogenously expressing FMRP (wild-type) have fewer synapses than neighboring Fmr1 KO neurons. An intact K homology domain 2 (KH2) RNA-binding domain and dephosphorylation of FMRP at S500 were required for the effects of FMRP on synapse number, indicating that FMRP interaction with RNA and translating polyribosomes leads to synapse loss.