Departments of Neurology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
KAN Research Institute, Inc., 6-8-2 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan.
Sci Rep. 2020 Mar 17;10(1):4857. doi: 10.1038/s41598-020-61676-x.
Mutations in RNA-binding proteins (RBPs) such as TAR DNA-binding protein 43 (TDP-43) and fused in sarcoma (FUS) are associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent evidence suggests that RNA dysregulation mediated by aberrant RBPs may play a critical role in neurodegeneration, but the underlying molecular mechanisms are largely unknown. In this study, we performed whole transcriptome profiling of various brain tissues of a transgenic (Tg) mouse model of ALS/FTD overexpressing the exogenous nuclear localization signal deletion mutant of human FUS (ΔNLS-FUS) to investigate changes associated with the early stages of ALS/FTD. Although there were not many differences in expression profiles between wild-type and Tg mice, we found that Sema3g was significantly upregulated in the frontal cortex and hippocampus of Tg mice. Interestingly, analysis of alternative splicing events identified widespread exons that were differentially regulated in Tg mice in a tissue-specific manner. Our study thus identified aberrant splicing regulation mediated by mutant FUS during the early stages of ALS/FTD. Targeting this aberrant splicing regulation represents a potential therapeutic strategy for ALS/FTD.
RNA 结合蛋白（RBPs）如 TAR DNA 结合蛋白 43（TDP-43）和肉瘤融合蛋白（FUS）的突变与肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）有关。最近的证据表明，由异常 RBPs 介导的 RNA 失调可能在神经退行性变中发挥关键作用，但潜在的分子机制在很大程度上尚不清楚。在这项研究中，我们对过度表达人 FUS 的核定位信号缺失突变体（ΔNLS-FUS）的 ALS/FTD 转基因（Tg）小鼠模型的各种脑组织进行了全转录组谱分析，以研究与 ALS/FTD 早期阶段相关的变化。尽管野生型和 Tg 小鼠之间的表达谱差异不大，但我们发现 Sema3g 在 Tg 小鼠的额皮质和海马体中显著上调。有趣的是，对可变剪接事件的分析确定了广泛的外显子，这些外显子在 Tg 小鼠中以组织特异性的方式受到差异调控。因此，我们的研究鉴定了 ALS/FTD 早期阶段由突变 FUS 介导的异常剪接调控。靶向这种异常剪接调控可能是 ALS/FTD 的一种潜在治疗策略。
