Nuclear TAR DNA-binding protein 43: A new target for amyotrophic lateral sclerosis treatment.
Nuclear TAR DNA-binding protein 43: A new target for amyotrophic lateral sclerosis treatment.
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核TAR DNA结合蛋白43：肌萎缩侧索硬化症治疗的新靶点
DOI：
10.3969/j.issn.1673-5374.2013.35.003
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发表时间：
2013-12-15
影响因子：
6.1
通讯作者：
Fan D
中科院分区：
文献类型：
--
作者：
Zheng M;Shi Y;Fan D
在肌萎缩侧索硬化症的变性神经元中可以检测到异常的TAR DNA结合蛋白43（TDP-43）包涵体。在这项研究中，我们诱导慢性氧化应激损伤丙二酸对培养的小鼠皮层运动神经元。在丙二酸损伤的后期，TDP-43在细胞核中的表达减少并转移到细胞质。这伴随着神经元死亡，模拟了肌萎缩侧索硬化症患者中观察到的TDP-43的病理变化。有趣的是，在对丙二酸盐处理的反应的早期阶段，核TDP-43表达增加，并且神经元保持相对完整，没有包涵体或碎片。因此，我们推测核TDP-43表达的增加可能是抗氧化应激损伤的促存活因子。体外转基因实验证实了这一假设，其中野生型小鼠TDP-43在培养的皮质运动神经元中的过表达显著降低了丙二酸诱导的神经元死亡。我们的研究结果表明，TDP-43的功能丧失是神经元变性的重要原因，上调TDP-43的核表达可能是肌萎缩侧索硬化症的神经保护作用。
Abnormal TAR DNA-binding protein 43 (TDP-43) inclusion bodies can be detected in the degenerative neurons of amyotrophic lateral sclerosis. In this study, we induced chronic oxidative stress injury by applying malonate to cultured mouse cortical motor neurons. In the later stages of the malonate insult, TDP-43 expression reduced in the nuclei and transferred to the cytoplasm. This was accompanied by neuronal death, mimicking the pathological changes in TDP-43 that are seen in patients with amyotrophic lateral sclerosis. Interestingly, in the early stages of the response to malonate treatment, nuclear TDP-43 expression increased, and neurons remained relatively intact, without inclusion bodies or fragmentation. Therefore, we hypothesized that the increase of nuclear TDP-43 expression might be a pro-survival factor against oxidative stress injury. This hypothesis was confirmed by an in vitro transgenic experiment, in which overexpression of wild type mouse TDP-43 in cultured cortical motor neurons significantly reduced malonate-induced neuronal death. Our findings suggest that the loss of function of TDP-43 is an important cause of neuronal degeneration, and upregulation of nuclear TDP-43 expression might be neuroprotective in amyotrophic lateral sclerosis.
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