Tracking the Fragile X Mental Retardation Protein in a Highly Ordered Neuronal RiboNucleoParticles Population: A Link between Stalled Polyribosomes and RNA Granules
Tracking the Fragile X Mental Retardation Protein in a Highly Ordered Neuronal RiboNucleoParticles Population: A Link between Stalled Polyribosomes and RNA Granules
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DOI：
10.1371/journal.pgen.1006192
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发表时间：
2016-07-01
期刊：
影响因子：
4.5
通讯作者：
Khandjian, Edouard W.
中科院分区：
文献类型：
--
作者：
El Fatimy, Rachid;Davidovic, Laetitia;Khandjian, Edouard W.
突触的局部翻译在神经元发育和活动依赖性突触可塑性中发挥着关键作用。 mRNA 作为被称为 RNA 颗粒的压缩核糖核颗粒从神经元胞体转移到远处的突触。它们含有许多 RNA 结合蛋白，包括脆性 X 型智力迟钝蛋白 (FMRP)，缺乏该蛋白会导致脆性 X 综合征，这是最常见的智力障碍遗传形式，也是自闭症的主要遗传原因。使用 FMRP 作为示踪剂，我们从小鼠脑匀浆中纯化了特定群体的 RNA 颗粒。蛋白质组成分析揭示了多聚核糖体和 RNA 颗粒之间的密切关系。然而，后者具有独特的建筑和结构特性，因为通过电子显微镜观察到它们被检测为紧密紧凑的结构，并且汇聚的证据表明这些结构可能是从停滞的多核糖体中出现的。延时视频显微镜表明，单个颗粒合并形成从胞体运输到远端位置的货物。转录组分析表明，参与细胞骨架重塑和神经发育的 mRNA 子集选择性地富集在 RNA 颗粒中。 FMRP 描述的假定 mRNA 靶标中有三分之一似乎在颗粒中运输，并且 FMRP 在颗粒中比在多核糖体中更丰富。这一观察结果支持 FMRP 在颗粒生物学中的主要作用。我们的研究结果为神经系统疾病（例如脆性 X 综合征）动物模型中 RNA 颗粒功能障碍的研究开辟了新途径。
Local translation at the synapse plays key roles in neuron development and activity-dependent synaptic plasticity. mRNAs are translocated from the neuronal soma to the distant synapses as compacted ribonucleoparticles referred to as RNA granules. These contain many RNA-binding proteins, including the Fragile X Mental Retardation Protein (FMRP), the absence of which results in Fragile X Syndrome, the most common inherited form of intellectual disability and the leading genetic cause of autism. Using FMRP as a tracer, we purified a specific population of RNA granules from mouse brain homogenates. Protein composition analyses revealed a strong relationship between polyribosomes and RNA granules. However, the latter have distinct architectural and structural properties, since they are detected as close compact structures as observed by electron microscopy, and converging evidence point to the possibility that these structures emerge from stalled polyribosomes. Time-lapse video microscopy indicated that single granules merge to form cargoes that are transported from the soma to distal locations. Transcriptomic analyses showed that a subset of mRNAs involved in cytoskeleton remodelling and neural development is selectively enriched in RNA granules. One third of the putative mRNA targets described for FMRP appear to be transported in granules and FMRP is more abundant in granules than in polyribosomes. This observation supports a primary role for FMRP in granules biology. Our findings open new avenues for the study of RNA granule dysfunctions in animal models of nervous system disorders, such as Fragile X syndrome.