星型胶质细胞上调基因-1（AEG-1）调控应激颗粒形成在肌萎缩侧索硬化疾病中的机制研究

Dynamic abnormalities of stress granules (SGs) are closely related to aging and the development of amyotrophic lateral sclerosis (ALS). Astrocyte elevated gene-1 (AEG-1) regulates multiple signaling pathways involved in the formation of SGs, but its role in ALS is still unclear. Our previous studies suggest that, under acute stress conditions, low expression of AEG-1 in motor neurons of ALS may inhibit the formation of SGs, and thus led to motor neuron degeneration; however, the high expression of AEG-1 in ALS astrocytes, through its mediated neuroinflammatory and excitotoxic effects, can promote the segregation of Hsp70 mRNA into SGs in motor neurons, inhibiting the translation of Hsp70 and further aggravating the degeneration of motor neurons. The aim of this study is to explore whether AEG-1 regulates the formation of SGs and its associated molecular mechanism in different cell subtypes related to aging and ALS. Moreover, targeted gene silencing and overexpression in vitro and in vivo will be applied in our study to explore the regulation of AEG-1 on stress granules under different stress conditions in ALS. We hope that this study will provide new target for intervention in ALS or other aging-related diseases.

应激颗粒（SGs）动力学异常与衰老和肌萎缩侧索硬化（ALS）发生发展密切相关。星型胶质细胞上调基因-1（AEG-1）可调控SGs形成的多种信号通路，但在ALS中所发挥的作用尚不清楚。本课题组前期工作提示:急性应激条件下ALS运动神经元中低表达的AEG-1可使SGs形成受阻进而导致运动神经元变性死亡；而ALS星型胶质细胞中高表达的AEG-1通过其神经炎性反应和兴奋性毒性作用，可促进运动神经元内Hsp70mRNA隔离入SGs中，抑制其翻译进一步加重运动神经元的变性死亡。本课题旨在探索AEG-1对衰老及ALS发病相关的不同细胞亚型的SGs是否存在调控作用及其分子机制；并分别靶向过表达ALS小鼠运动神经元中AEG-1及靶向沉默ALS星型胶质细胞中AEG-1，探究其对ALS小鼠的影响。对阐明AEG-1调控SGs形成在ALS中的作用机制有重要意义，并可能为ALS或其他衰老相关疾病的干预提供新的靶点。

肌萎缩侧索硬化（Amyotrophic Lateral Sclerosis, ALS）是一种成年起病的致命性神经退行性疾病。许多ALS致病基因的突变可导致神经元内应激颗粒（SGs）的动力学异常并促进ALS中病理性蛋白聚集体的形成，最终导致神经元的变性和死亡。星型胶质细胞上调基因-1（AEG-1）与ALS的发生发展密切相关，作为一个具有多重功能的基因及蛋白，它能调控SGs形成的多种信号通路，但在ALS中所发挥的作用尚不清楚。本课题以ALS细胞和动物模型为主要研究对象，探索AEG-1对SGs的动力学变化是否存在调控作用及其分子机制，并通过给予不同应激刺激，观察AEG-1对ALS神经元存活的影响。我们的结果显示，在hSOD1G93A转基因ALS小鼠脊髓前角运动神经元和体外细胞模型中均存在SGs的形成，且突变的SOD1(G93A)可以与SGs共定位。此外，我们证实了AEG-1是SGs的一个新组分，且调控AEG-1能够影响SGs的形成和和解聚。更重要的是，AEG-1能够通过对SGs动力学的调控促进ALS神经元在各种应激条件下的存活。本课题的研究结果表明AEG-1通过调控SGs的动力学变化在ALS神经元中发挥重要的神经保护作用，很可能为ALS或其他衰老相关疾病的干预提供新的靶点。