TDP-43 is an RNA-binding protein that forms cytoplasmic aggregates in multiple neurodegenerative diseases. Although the loss of normal TDP-43 functions likely contributes to disease pathogenesis, the cell biological consequences of human TDP-43 depletion are not well understood. We, therefore, generated human TDP-43 knockout (KO) cells and subjected them to parallel cell biological and transcriptomic analyses. These efforts yielded three important discoveries. First, complete loss of TDP-43 resulted in widespread morphological defects related to multiple organelles, including Golgi, endosomes, lysosomes, mitochondria, and the nuclear envelope. Second, we identified a new role for TDP-43 in controlling mRNA splicing of Nup188 (nuclear pore protein). Third, analysis of multiple amyotrophic lateral sclerosis causing TDP-43 mutations revealed a broad ability to support splicing of TDP-43 target genes. However, as some TDP-43 disease-causing mutants failed to fully support the regulation of specific target transcripts, our results raise the possibility of mutation-specific loss-of-function contributions to disease pathology.

中文翻译：

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人类TDP-43在细胞和细胞器动态平衡调节中的多效性要求。

TDP-43是一种RNA结合蛋白，可在多种神经退行性疾病中形成细胞质聚集体。尽管正常TDP-43功能的丧失可能是疾病的发病机理，但人类TDP-43耗竭的细胞生物学后果尚不十分清楚。因此，我们生成了人类TDP-43基因敲除（KO）细胞，并对其进行了平行细胞生物学和转录组学分析。这些努力产生了三个重要发现。首先，TDP-43的完全丧失导致与多个细胞器（包括高尔基体，内体，溶酶体，线粒体和核膜）有关的广泛形态学缺陷。其次，我们确定了TDP-43在控制Nup188（核孔蛋白）的mRNA剪接中的新作用。第三，引起TDP-43突变的多发肌萎缩性侧索硬化的分析显示，支持TDP-43靶基因剪接的广泛能力。但是，由于某些TDP-43致病突变体无法完全支持特定靶标转录物的调控，因此我们的结果提出了突变特异性功能丧失对疾病病理的贡献的可能性。