SecinH3 Attenuates TDP-43 p.Q331K-Induced Neuronal Toxicity by Suppressing Endoplasmic Reticulum Stress and Enhancing Autophagic Flux
SecinH3 Attenuates TDP-43 p.Q331K-Induced Neuronal Toxicity by Suppressing Endoplasmic Reticulum Stress and Enhancing Autophagic Flux
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SecinH3 通过抑制内质网应激和增强自噬通量来减轻 TDP-43 p.Q331K 诱导的神经元毒性
DOI：
10.1002/iub.1951
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发表时间：
2019-02-01
期刊：
影响因子：
4.6
通讯作者：
Lu, Hong
中科院分区：
文献类型：
--
作者：
Hu, Wentao;Liu, Xi;Lu, Hong
肌萎缩侧索硬化症(ALS)是一种致命性、成人发病的神经退行性疾病。反式激活反应区DNA结合蛋白43(TDP-43)P.Q331K突变(TDP-43 Q331K)是ALS中的一种具有神经毒性的致病突变。SecinH3是一种细胞粘附素抑制剂，对突变型超氧化物歧化酶1(SOD1)毒性具有神经保护作用。然而，SecinH3是否对突变型TDP-43p.Q331K蛋白的毒性具有保护作用及其可能的分子机制尚未被研究。为确定TDP-43 Q331K是否具有神经元毒性作用，选用人源性神经细胞系SH-SY5Y作为体外神经元功能模型。将TDP-43野生型或TDP-43 Q331K瞬时导入SH-SY5Y细胞。值得注意的是，TDP-43 Q331K通过内质网(ER)应激介导的细胞凋亡和自噬通量的损害而诱导神经元损伤。SecinH3通过抑制内质网应激诱导的细胞凋亡和增强自噬通量，成功地减轻了TDP-43 Q331K诱导的神经元毒性。综上所述，我们的体外研究为SecinH3对TDP-43 Q331K介导的神经元毒性具有神经保护作用提供了证据，并能够阐明其作用机制。因此，SecinH3可以被认为是一种很有前途的ALS治疗剂。(C)2018年IUBMB Life，71(1)：192-199,2019年
Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset, neurodegenerative disease. The transactivating response region DNA binding protein 43 (TDP-43) p.Q331K mutation (TDP-43 Q331K) has previously been identified in ALS as a disease-causing mutation with neurotoxicity. SecinH3, a cytohesin inhibitor, has neuroprotective effects against mutant superoxide dismutase 1 (SOD1) toxicity. However, whether SecinH3 protects against mutant TDP-43 p.Q331K protein toxicity and its potential molecular mechanisms have not yet been investigated. To determine whether TDP-43 Q331K induces neuronal toxicity, SH-SY5Y, a human derived neuronal cell line were selected as an in vitro model of neuronal function. SH-SY5Y cells were transiently transfected with TDP-43 wild-type or TDP-43 Q331K. Remarkably, TDP-43 Q331K induced neuronal damage via endoplasmic reticulum (ER) stress-mediated apoptosis and the impairment of the autophagic flux. SecinH3 was demonstrated to successfully attenuate the TDP-43 Q331K-induced neuronal toxicity by suppressing ER stress-mediated apoptosis and enhancing the autophagic flux. Taken together, our in vitro study provided evidence that SecinH3 exerts neuroprotective effects against TDP-43 Q331K-mediated neuronal toxicity and was able to elucidate its mode of action. SecinH3 could, therefore, be considered a promising candidate as a therapeutic agent of ALS. (c) 2018 IUBMB Life, 71(1):192-199, 2019