FMRP蛋白通过调控RNP颗粒形成及运输影响脆性X染色体综合征神经元兴奋性的机制研究

脆性X染色体综合征（FXS）是最常见的遗传性单基因智力障碍疾病之一，由FMRP蛋白缺失引起，在神经元模型中，FMRP缺失导致神经元兴奋性异常，但机制尚未阐明。FMRP是RNA结合蛋白，申请者前期研究表明，FMRP在人神经细胞中结合大量mRNA，但FMRP如何调控这些靶mRNA进而影响神经元兴奋性仍不明确，该调控机制对阐明FXS疾病发生机制有关键意义。申请者近期研究显示，FMRP分布于神经突起的RNP颗粒中，且可影响RNP颗粒形成。申请者由此推测，FMRP通过调控RNP颗粒影响其靶mRNA及神经元功能。本研究拟利用高清荧光显微成像、活细胞荧光成像等技术，深入探讨：1）FMRP调控神经元中RNP颗粒的形成；2）FMRP通过与马达蛋白相互作用调控RNP颗粒的运输；3）RNP颗粒异常导致FXS神经元兴奋性异常。研究结果将促进了解FMRP调控其靶mRNA的分子机制，帮助阐明FXS的疾病发生机制。

Fragile X Syndrome (FXS) is one of the most common inherited intellectual disability. FXS is caused by loss of FMRP protein. In FXS neuron models, loss of FMRP leads to neuronal hyperexcitability. However, the mechanisms underlying FXS and neuronal hyperexcitability are unclear. FMRP is an RNA-binding protein. Our previous studies indicate that FMRP binds many mRNAs in human neural cells. However, as a key question in understanding FXS, how FMRP regulates its target mRNAs is not fully understood. Our pilot experiments suggest that FMRP is localized in ribonucleoprotein (RNP) granules in human neurons. And latest publications show that FMRP facilitate formation of RNP granule-like droplets in cell-free solutions. Therefore, we hypothesize that FMRP regulates neuronal activities through modulating RNP granules. In this proposal, we plan to explore mechanisms underlying FMRP regulation of RNP granules and the contribution of RNP granules dysregulation to neuronal hyperexcitability, including: 1) regulation of RNP granule formation by FMRP; 2) regulation of RNP granule transportation by FMRP through interaction with motor proteins; 3) contribution of RNP granule abnormality to neuronal hyperexcitability in FXS. This study will help further understand the mechanisms underlying regulation of mRNAs by FMRP and provide insights into molecular and cellular mechanisms underlying FXS.