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首页> 外文期刊>Neuroscience Research: The Official Journal of the Japan Neuroscience Society >Fragile X mental retardation protein regulates accumulation of the active zone protein Munc18-1 in presynapses via local translation in axons during synaptogenesis
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Fragile X mental retardation protein regulates accumulation of the active zone protein Munc18-1 in presynapses via local translation in axons during synaptogenesis

机译：脆弱的X精神迟发蛋白通过局部翻译在Syshaptogis期间通过局部翻译来调节Pressynapses中的积极区域蛋白质munc18-1的积累

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摘要

Fragile X mental retardation protein (FMRP), a causative gene (FMR1) product of Fragile X syndrome (FXS), is an RNA-binding protein to regulate local protein synthesis in dendrites for postsynaptic functions. However, involvement of FMRP in local protein synthesis in axons for presynaptic functions remains unclear. Here we investigated role of FMRP in local translation of the active zone protein Munc18-1 during presynapse formation. We found that leucine-rich repeat transmembrane neuronal 2 (LRRTM2)-conjugated beads, which promotes synchronized presynapse formation, induced simultaneous accumulation of FMRP and Munc18-1 in presynapses of axons of mouse cortical neurons in neuronal cell aggregate culture. The LRRTM2-induced accumulation of Munc18-1 in presynapses was observed in axons proteinsynthesis-dependently, even physically separated from cell bodies. The accumulation of Munc18-1 was enhanced in Fmr1-knockout (KO) axons as compared to wild type (WT), suggesting FMRP-regulated suppression for local translation of Munc18-1 in axons during presynapse formation. Using naturally formed synapses of dissociated culture, structured illumination microscope revealed that accumulation of Munc18-1 puncta in Fmr1-KO neurons increased significantly at 19 days in vitro, as compared to WT. Our findings lead the possibility that excessive accumulation of Munc18-1 in presynapses at early stage of synaptic development in Fmr1-KO neurons may have a critical role in impaired presynaptic functions in FXS. (C) 2018 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.
机译：脆弱的X精神迟滞蛋白（FMRP），易易甲综合征（FXS）的致病基因（FMR1）产物，是RNA结合蛋白，以调节突触态函数的树突中的局部蛋白质合成。然而，对突触前职能轴突中局部蛋白质合成的涉及FMRP仍不清楚。在这里，我们研究了FMRP在预先形成期间局部翻译的作用。我们发现富含亮氨酸的重复跨膜神经元2（LRRTM2） - 缀合的珠子，其促进了在神经元细胞聚集培养中小鼠皮质神经元轴突的轴突中同步的FMRP和Munc18-1的同步积聚。在轴突蛋白合成的依赖性中，在轴突中观察到预先存在的LRRTM2诱导的Munc18-1诱导的累积，甚至与细胞体积物理分离。与野生型（WT）相比，在FMR1敲除（KO）轴突中，在FMR1敲除（KO）轴突中增强了Munc18-1的累积，表明在预先跨越式形成期间Munc18-1在轴突中局部翻译的FMRP调节抑制。使用异常形成的解离培养的突触，结构化照明显微镜显示，与wt相比，在体外，FMR1-Ko神经元中的Munc18-1斑点的积累显着增加。我们的研究结果导致FMR1-KO神经元突触发育早期突触阶段的过早积累的可能性可能在FXS中的突触障碍障碍中具有关键作用。 （c）2018年Elsevier B.V.和日本神经科学社会。版权所有。

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