Traumatic injury compromises nucleocytoplasmic transport and leads to TDP-43 pathology.
Traumatic injury compromises nucleocytoplasmic transport and leads to TDP-43 pathology.
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DOI：
10.7554/elife.67587
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发表时间：
2021-05-26
期刊：
影响因子：
7.7
通讯作者：
Pandey UB
中科院分区：
文献类型：
--
作者：
Anderson EN;Morera AA;Kour S;Cherry JD;Ramesh N;Gleixner A;Schwartz JC;Ebmeier C;Old W;Donnelly CJ;Cheng JP;Kline AE;Kofler J;Stein TD;Pandey UB
创伤性脑损伤（TBI）是许多神经退行性疾病的诱发因素，包括肌萎缩侧索硬化症（ALS）、阿尔茨海默病（AD）、帕金森病（PD）和慢性创伤性脑病（CTE）。尽管核细胞质转运 (NCT) 缺陷已被报道为 ALS 和其他神经退行性疾病，但 NCT 缺陷是否发生在 TBI 中仍不清楚。我们对暴露于重复 TBI 的果蝇进行了蛋白质组学分析，并鉴定了几种新分子途径的变化。 TBI 上调核孔复合物 (NPC) 和核细胞质转运 (NCT) 蛋白，并改变核孔蛋白稳定性。创伤性损伤破坏了果蝇和大鼠模型中 RanGAP1 和 NPC 蛋白的分布，并导致 NPC 成分和 TDP-43 共聚集。此外，核输出抑制剂可以挽救创伤介导的 NCT 缺陷和致死率。重要的是，体内和体外核孔蛋白的遗传上调引发了 TDP-43 细胞质的错误定位、聚集和溶解度改变，并降低了动物的运动功能和寿命。我们还发现轻度或重度 CTE 患者死后脑组织中 NUP62 病理学和 NUP62 浓度升高，以及 NUP62 和 TDP-43 在 CTE 中的共定位。这些发现表明，TBI 会导致 NCT 缺陷，从而可能介导 CTE 中的 TDP-43 病理。
Traumatic brain injury (TBI) is a predisposing factor for many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Parkinson’s disease (PD), and chronic traumatic encephalopathy (CTE). Although defects in nucleocytoplasmic transport (NCT) is reported ALS and other neurodegenerative diseases, whether defects in NCT occur in TBI remains unknown. We performed proteomic analysis on Drosophila exposed to repeated TBI and identified resultant alterations in several novel molecular pathways. TBI upregulated nuclear pore complex (NPC) and nucleocytoplasmic transport (NCT) proteins as well as alter nucleoporin stability. Traumatic injury disrupted RanGAP1 and NPC protein distribution in flies and a rat model and led to coaggregation of NPC components and TDP-43. In addition, trauma-mediated NCT defects and lethality are rescued by nuclear export inhibitors. Importantly, genetic upregulation of nucleoporins in vivo and in vitro triggered TDP-43 cytoplasmic mislocalization, aggregation, and altered solubility and reduced motor function and lifespan of animals. We also found NUP62 pathology and elevated NUP62 concentrations in postmortem brain tissues of patients with mild or severe CTE as well as co-localization of NUP62 and TDP-43 in CTE. These findings indicate that TBI leads to NCT defects, which potentially mediate the TDP-43 pathology in CTE.