TDP-43 depletion: mechanism of neuronal cell death in ALS
TDP-43 depletion: mechanism of neuronal cell death in ALS
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DOI：
10.2217/fnl-2018-0010
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发表时间：
2018-08
期刊：
影响因子：
1.3
通讯作者：
Akira Kitamura
中科院分区：
文献类型：
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作者：
Akira Kitamura
反式激活反应DNA/RNA结合蛋白43 kDa（TDP-43）调节RNA剪接和稳定性。TDP-43是肌萎缩侧索硬化症患者运动神经元的泛素阳性包涵体的组分，表明在疾病发病机制中的作用。毒性细胞内TDP-43聚集可导致神经元细胞死亡。TDP-43在动物模型中的缺失导致早期发育中的致死性。此外，成年动物和细胞中的TDP-43敲低增加了异常剪接。在TDP-43敲低的神经母细胞瘤细胞和肌萎缩侧索硬化症的运动神经元中，富含尿苷的小核RNA（U snRNA）调节被破坏。异常的mRNA剪接和U snRNA表达可能是神经元细胞死亡的关键过程。本文综述了TDP-43缺失导致的异常剪接的研究历史和前景。
Trans activation response DNA/RNA-binding protein 43 kDa (TDP-43) regulates RNA splicing and stability. TDP-43 is a component of ubiquitin-positive inclusion bodies of motor neurons from patients with amyotrophic lateral sclerosis, suggesting a role in disease pathogenesis. Toxic intracellular TDP-43 aggregation may cause neuronal cell death. The loss of TDP-43 in animal models causes lethality in early development. Furthermore, TDP-43 knockdown in adult animals and cells increases aberrant splicing. Uridine-rich small nuclear RNA (U snRNA) regulation is disrupted in cultured neuroblastoma cells with TDP-43 knockdown and in motor neurons in amyotrophic lateral sclerosis. Aberrant mRNA splicing and U snRNA expression are likely key processes in neuronal cell death. We review the research history and future perspectives of aberrant splicing by TDP-43 loss.