Persistent mRNA localization defects and cell death in ALS neurons caused by transient cellular stress.
Persistent mRNA localization defects and cell death in ALS neurons caused by transient cellular stress.
复制标题
由短暂的细胞应激引起的 ALS 神经元中持续的 mRNA 定位缺陷和细胞死亡。
DOI：
10.1016/j.celrep.2021.109685
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发表时间：
2021
期刊：
影响因子：
8.8
通讯作者：
Yeo,GeneW
中科院分区：
文献类型：
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作者：
Markmiller,Sebastian;Sathe,Shashank;Server,KariL;Nguyen,ThaiB;Fulzele,Amit;Cody,Neal;Javaherian,Ashkan;Broski,Sara;Finkbeiner,Steven;Bennett,EricJ;Lécuyer,Eric;Yeo,GeneW
含有RNA结合蛋白（rbp）的持续细胞质聚集体是迟发性神经退行性疾病（如肌萎缩侧索硬化症（ALS））发病机制的核心。这些聚集体与应激诱导的RNA颗粒（SGs）共享成分、分子机制和细胞蛋白质量控制途径。在这里，我们利用亚细胞分离、RNA测序和蛋白质组学评估了应激对人类多能干细胞源性运动神经元（PSC-MNs） mRNA定位格局的影响。短暂的应激破坏亚细胞RNA和蛋白质的分布，改变SG和als相关rbp的RNA结合谱，重现疾病相关的分子变化，如stmn2的异常剪接。虽然神经典型的PSC-MNs在从应激中恢复后会重建正常的亚细胞定位景观，但携带als相关突变的细胞是不妥协的，并表现出神经元细胞死亡的延迟性增加。我们的研究结果强调了亚细胞分子分布作为预测特征，并强调了细胞应激作为研究als相关机制范例的效用。
Persistent cytoplasmic aggregates containing RNA binding proteins (RBPs) are central to the pathogenesis of late-onset neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). These aggregates share components, molecular mechanisms, and cellular protein quality control pathways with stress-induced RNA granules (SGs). Here, we assess the impact of stress on the global mRNA localization landscape of human pluripotent stem cell-derived motor neurons (PSC-MNs) using subcellular fractionation with RNA sequencing and proteomics. Transient stress disrupts subcellular RNA and protein distributions, alters the RNA binding profile of SG- and ALS-relevant RBPs and recapitulates disease-associated molecular changes such as aberrant splicing ofSTMN2. Although neurotypical PSC-MNs re-establish a normal subcellular localization landscape upon recovery from stress, cells harboring ALS-linked mutations are intransigent and display a delayed-onset increase in neuronal cell death. Our results highlight subcellular molecular distributions as predictive features and underscore the utility of cellular stress as a paradigm to study ALS-relevant mechanisms.