SMN驱动神经细胞轴突中mRNA转运核糖核蛋白形成的分子机制

脊髓性肌萎缩症（Spinal muscular atrophy，SMA）的致病原因是人基因组上编码SMN蛋白的SMN1基因缺失或突变，并伴随神经元细胞轴突中mRNA的分布异常。轴突中负责运输mRNA的核糖核蛋白复合体是由蛋白和mRNA通过“液-液分离相变”形成的无膜细胞器。我们的前期研究显示，SMN和FUS共定位在细胞质的无膜液滴中，这种共定位依赖于FUS的甲基化和SMN的寡聚。在体外实验中，SMN也能通过与甲基化FUS的多价互作促进其相变。拟运用RNA原位杂交，免疫荧光染色、免疫沉淀等实验手段，继续探讨SMN多价互作模型的普遍性，以及多价互作通过调控mRNA轴突转运和翻译，调控神经元轴突分化表型的机制。该研究有助于揭示神经细胞中mRNP相变形成的分子机制，为研究SMA的发病机理提供新的思路。

Spinal muscular atrophy (SMA) is caused by deletion or mutation of SMN1 gene encoding SMN protein in human genome,accompanied by abnormal distribution of mRNA in axons of neurons.The mRNA ribonucleoprotein (mRNP) responsible for the transport of mRNA in axons is a membrane-free organelle formed by the "liquid-liquid phase separation"of protein and mRNA. Our previous studies showed that SMN and Fus colocalized in membraneless droplets, which depended on the methylation of FUS and the oligomeric domain of SMN. In vitro, SMN can also promote the phase separation of methylated Fus by protein-protein multivalent interaction. We intend to use RNA in situ hybridization, immunofluorescence staining, immunoprecipitation and other experimental methods to continue to explore the universality of the multivalent interaction model of SMN, and the mechanism of multivalent interaction regulating neuronal axon differentiation phenotype through regulating mRNA axon transport and translationThis study will help to reveal the molecular mechanism of mRNP phase separation in neuron cells, and provide new ideas for the study of the pathogenesis of SMA.