A gain of toxic function hypothesis via accumulated RNA-binding protein and repeat RNA in the pathogenesis of ALS and its validation in vivo

基于RNA的异常积累会引发RNA结合蛋白的聚集和积累，最终导致肌萎缩性侧索硬化症（ALS）发病过程中的神经退行性变的假设，1)我们建立了表达扩增的GGGGCC重复RNA的新型ALS模型果蝇，其模拟了人类ALS患者的神经表型和病理。2)此外，利用新建立的ALS模型蝇，我们成功地鉴定了一些RNA结合蛋白，可以在体内修饰扩增的GGGGCC重复RNA的毒性。因此，我们认为RNA结合蛋白参与了异常RNA积累的神经毒性，这可能有助于ALS的病理机制。

Based on the hypothesis that abnormal accumulation of RNA would trigger aggregation and accumulation of the RNA-binding proteins, eventually leading to neurodegeneration in the pathogenesis of amyotrophic lateral sclerosis (ALS), 1) we established novel ALS model flies expressing expanded GGGGCC repeat RNA, which mimic neurological phenotypes and pathology of human ALS patients. 2) Furthermore, using this newly-established ALS models flies, we have successfully identified some RNA-binding proteins that can modify the toxicity of expanded GGGGCC repeat RNA in vivo. We therefore conclude that RNA-binding proteins are involved in neurotoxicity of abnormal RNA accumulation, which can contribute to the pathomechanism of ALS.