Synaptic regulation of protein synthesis and the fragile X protein
Synaptic regulation of protein synthesis and the fragile X protein
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DOI：
10.1073/pnas.141145998
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发表时间：
2001-06-19
影响因子：
11.1
通讯作者：
Weiler, IJ
中科院分区：
文献类型：
--
作者：
Greenough, WT;Klintsova, AY;Weiler, IJ
蛋白质合成发生在神经元树突中，通常在突触附近。多核糖体聚集体经常出现在树突棘中，特别是在发育过程中。在经验依赖性突触发生期间，棘中的多核糖体聚集体增加，例如，在复杂的环境中。有些蛋白质的合成似乎直接受突触活动的调节。我们用“突触神经体。“一种高度富集夹断的、重新密封的突触前过程的制剂，所述突触前过程连接到重新密封的突触后过程，所述突触后过程保留神经递质释放、受体激活和各种突触后反应（包括信号传导途径和蛋白质合成）的正常功能。我们已经发现，当突触神经体被谷氨酸或I组代谢型谷氨酸受体激动剂如二羟苯甘氨酸刺激时。mRNA被迅速吸收到多核糖体聚集体中，标记的甲硫氨酸被掺入蛋白质中。合成的蛋白质之一是FMRP。在脆性X染色体智力迟钝综合症中减少或缺失的蛋白质。FMRP具有三个RNA结合结构域，据报道与大量mRNA结合。我们发现，在脆性X综合征的敲除小鼠模型中，突触神经小体中二羟苯甘氨酸激活的蛋白质合成显著减少，该模型不能产生全长FMRP，这表明FMRP参与或需要此过程。对脆性X综合征患者尸检样本的研究表明，树突棘可能无法呈现正常的成熟尺寸和形状，并且在患者样本中每单位树突长度有更多的棘。对基因敲除小鼠的研究也发现了类似的脊柱大小和形状。对含有处理触须信息的桶状细胞排列的体感皮层区域发育的研究表明，基因敲除小鼠的正常树突退化受损。这一发现表明，FMRP可能需要正常的成熟和消除过程中发生在大脑皮层发育。
Protein synthesis occurs in neuronal dendrites, often near synapses. Polyribosomal aggregates often appear in dendritic spines, particularly during development. Polyribosomal aggregates in spines increase during experience-dependent synaptogenesis, e.g., in rats in a complex environment. Some protein synthesis appears to be regulated directly by synaptic activity. We use "synaptoneurosomes." a preparation highly enriched in pinched-off, resealed presynaptic processes attached to resealed postsynaptic processes that retain normal functions of neurotransmitter release, receptor activation, and various postsynaptic responses including signaling pathways and protein synthesis. We have found that, when synaptoneurosomes are stimulated with glutamate or group I metabotropic glutamate receptor agonists such as dihydroxyphenylglycine. mRNA is rapidly taken up into polyribosomal aggregates, and labeled methionine is incorporated into protein. One of the proteins synthesized is FMRP. the protein that is reduced or absent in fragile X mental retardation syndrome. FMRP has three RNA-binding domains and reportedly binds to a significant number of mRNAs. We have found that dihydroxyphenylglycine-activated protein synthesis in synaptoneurosomes is dramatically reduced in a knockout mouse model of fragile X syndrome, which cannot produce full-length FMRP, suggesting that FMRP is involved in or required for this process. Studies of autopsy samples from patients with fragile X syndrome have indicated that dendritic spines may fail to assume a normal mature size and shape and that there are more spines per unit dendrite length in the patient samples. Similar findings on spine size and shape have come from studies of the knockout mouse. Study of the development of the somatosensory cortical region containing the barrel-like cell arrangements that process whisker information suggests that normal dendritic regression is impaired in the knockout mouse. This finding suggests that FMRP may be required for the normal processes of maturation and elimination to occur in cerebral cortical development.