TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD.
TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD.
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DOI：
10.1038/s41593-017-0047-3
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发表时间：
2018-03
影响因子：
25
通讯作者：
Rossoll W
中科院分区：
文献类型：
--
作者：
Chou CC;Zhang Y;Umoh ME;Vaughan SW;Lorenzini I;Liu F;Sayegh M;Donlin-Asp PG;Chen YH;Duong DM;Seyfried NT;Powers MA;Kukar T;Hales CM;Gearing M;Cairns NJ;Boylan KB;Dickson DW;Rademakers R;Zhang YJ;Petrucelli L;Sattler R;Zarnescu DC;Glass JD;Rossoll W
TAR dna结合蛋白43 （TDP-43）的细胞质错定位和聚集是肌萎缩侧索硬化症和额颞叶痴呆谱系（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，我们使用邻近依赖生物素鉴定（BioID）来研究洗涤剂不溶性TDP-43聚集体的相互作用，发现它们富含核孔复合物（NPC）和核胞质运输机制的成分。聚集和疾病相关突变体TDP-43触发核孔蛋白（Nups）和运输因子（TFs）的隔离和/或错定位，并干扰小鼠原代皮质神经元、人成纤维细胞和ipsc衍生神经元的核蛋白输入和RNA输出。散发性ALS患者（sALS）和TARDBP （TDP-ALS）和C9orf72 （C9-ALS）基因突变患者的脑组织中存在核孔病理。我们的数据强烈暗示tdp -43介导的核胞质转运缺陷是ALS/FTD的常见疾病机制。
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 (NPC) and nucleocytoplasmic transport machinery. Aggregated and disease-linked mutant TDP-43 triggered the sequestration and/or mislocalization of nucleoporins (Nups) and transport factors (TFs), and interfered with nuclear protein import and RNA export in mouse primary cortical neurons, human fibroblasts, and iPSC-derived neurons. Nuclear pore pathology is present in brain tissue from sporadic ALS cases (sALS) and those with genetic mutations in TARDBP (TDP-ALS) and C9orf72 (C9-ALS). Our data strongly implicate TDP-43-mediated nucleocytoplasmic transport defects as a common disease mechanism in ALS/FTD.
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影响因子：
15.1
作者：
Fallini C;Bassell GJ;Rossoll W
通讯作者：
Rossoll W
影响因子：
3.5
作者：
Joardar, Archi;Menzl, Judith;Zarnescu, Daniela C.
通讯作者：
Zarnescu, Daniela C.
影响因子：
4
作者：
Ayala, Youhna M.;Zago, Paola;Baralle, Francisco E.
通讯作者：
Baralle, Francisco E.
影响因子：
16.2
作者：
Alami NH;Smith RB;Carrasco MA;Williams LA;Winborn CS;Han SSW;Kiskinis E;Winborn B;Freibaum BD;Kanagaraj A;Clare AJ;Badders NM;Bilican B;Chaum E;Chandran S;Shaw CE;Eggan KC;Maniatis T;Taylor JP
通讯作者：
Taylor JP
影响因子：
2.3
作者：
Halfmann R;Wright JR;Alberti S;Lindquist S;Rexach M
通讯作者：
Rexach M