TDP-43 regulates the alternative splicing of hnRNPA1 to yield an aggregation-prone variant in amyotrophic lateral sclerosis
TDP-43 regulates the alternative splicing of hnRNPA1 to yield an aggregation-prone variant in amyotrophic lateral sclerosis
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DOI：
10.1093/brain/awy062
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发表时间：
2018-05-01
期刊：
影响因子：
14.5
通讯作者：
Vande Velde, Christine
中科院分区：
文献类型：
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作者：
Deshaies, Jade-Emmanuelle;Shkreta, Lulzim;Vande Velde, Christine
RNA结合蛋白TDP-43（由TARDBP编码）和hnRNPA 1（HNRNPA 1）在某些肌萎缩侧索硬化症病例中均发生突变，并且经常错误定位于受影响患者运动神经元内的细胞质聚集体中。在大多数肌萎缩侧索硬化病例和近一半的额颞叶痴呆病例中观察到TDP-43的细胞质内含物，其伴随着细胞核TDP-43的耗竭。在这里，我们报告说，TDP-43结合HNRNPA 1前mRNA，并调节其剪接，并在HNRNPA 1转录盒外显子的增加，并因此升高的蛋白水平的一个亚型包含一个延长的朊病毒样结构域，称为hnRNP A1 B的核TDP-43的消耗的结果。结合体内和体外方法证明了hnRNP A1 B的更大的絮凝倾向，其驱动蛋白质聚集并且对细胞有毒。此外，有记录的TDP-43病理学的肌萎缩侧索硬化症患者显示神经元hnRNP A1 B细胞质积聚，这表明TDP-43错误定位可能通过改变HNRNPA 1前体mRNA剪接和功能而导致神经元脆弱性和丧失。鉴于TDP-43和hnRNP A1各自结合并因此调节三分之一的转录组，我们的数据表明RNA代谢的破坏比以前考虑的要广泛得多。
The RNA binding proteins TDP-43 (encoded by TARDBP) and hnRNP A1 (HNRNPA1) are each mutated in certain amyotrophic lateral sclerosis cases and are often mislocalized in cytoplasmic aggregates within motor neurons of affected patients. Cytoplasmic inclusions of TDP-43, which are accompanied by a depletion of nuclear TDP-43, are observed in most amyotrophic lateral sclerosis cases and nearly half of frontotemporal dementia cases. Here, we report that TDP-43 binds HNRNPA1 pre-mRNA and modulates its splicing, and that depletion of nuclear TDP-43 results in increased inclusion of a cassette exon in the HNRNPA1 transcript, and consequently elevated protein levels of an isoform containing an elongated prion-like domain, referred to as hnRNP A1B. Combined in vivo and in vitro approaches demonstrated greater fibrillization propensity for hnRNP A1B, which drives protein aggregation and is toxic to cells. Moreover, amyotrophic lateral sclerosis patients with documented TDP-43 pathology showed neuronal hnRNP A1B cytoplasmic accumulation, indicating that TDP-43 mislocalization may contribute to neuronal vulnerability and loss via altered HNRNPA1 pre-mRNA splicing and function. Given that TDP-43 and hnRNP A1 each bind, and thus modulate, a third of the transcriptome, our data suggest a much broader disruption in RNA metabolism than previously considered.