The cytoplasmic mislocalization and aggregation of TAR DNA-binding protein-43 (TDP-43) is a common histopathological hallmark of the amyotrophic lateral sclerosis and frontotemporal dementia disease spectrum (ALS/FTD). However, the composition of aggregates and their contribution to the disease process remain unknown. Here we used proximity-dependent biotin identification (BioID) to interrogate the interactome of detergent-insoluble TDP-43 aggregates and found them enriched for components of the nuclear pore complex and nucleocytoplasmic transport machinery. Aggregated and disease-linked mutant TDP-43 triggered the sequestration and/or mislocalization of nucleoporins and transport factors, and interfered with nuclear protein import and RNA export in mouse primary cortical neurons, human fibroblasts and induced pluripotent stem cell-derived neurons. Nuclear pore pathology is present in brain tissue in cases of sporadic ALS and those involving genetic mutations in TARDBP and C9orf72. Our data strongly implicate TDP-43-mediated nucleocytoplasmic transport defects as a common disease mechanism in ALS/FTD.

中文翻译：

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TDP-43 病理学破坏了 ALS/FTD 中的核孔复合物和核质转运。

TAR DNA 结合蛋白 43 (TDP-43) 的细胞质错误定位和聚集是肌萎缩侧索硬化和额颞叶痴呆疾病谱 (ALS/FTD) 的常见组织病理学标志。然而，聚集体的组成及其对疾病过程的贡献仍然未知。在这里，我们使用邻近依赖性生物素鉴定 (BioID) 来询问去污剂不溶性 TDP-43 聚集体的相互作用组，发现它们富含核孔复合物和核质转运机制的成分。聚集的和疾病相关的突变体 TDP-43 触发了核孔蛋白和转运因子的隔离和/或错误定位，并干扰了小鼠原代皮层神经元、人成纤维细胞和诱导多能干细胞衍生神经元中的核蛋白输入和 RNA 输出。在散发性 ALS 和涉及 TARDBP 和 C9orf72 基因突变的情况下，核孔病理学存在于脑组织中。我们的数据强烈暗示 TDP-43 介导的核质转运缺陷是 ALS/FTD 的常见疾病机制。