DAPK1 induces motor neuron apoptosis in hSOD1G93A-linked amyotrophic lateral sclerosis via regulating the Xiap/JNK pathway

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience Pub Date : 2025-07-14 DOI:10.1016/j.mcn.2025.104029

Xiaoli Su , Xingli Tan , Ying Wang , Weiwei Liang , Di Wang , Di Huo , Hongyong Wang , Yan Qi , Wenmo Zhang , Ling Han , Dongmei Zhang , Ming Wang , Jing Xu , Honglin Feng

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Abstract

Death-associated protein kinase 1 (DAPK1) is critically involved in regulating cell death in various neurodegenerative disorders. However, the role of DAPK1 in the pathogenesis of amyotrophic lateral sclerosis (ALS) remains unclear. Here, we found that the expression of DAPK1 significantly increased in ALS, showing a negative correlation with miR-501-3p. Upregulating DAPK1 led to an increase in motor neuron apoptosis by inhibiting Xiap. Conversely, silencing of DAPK1 protected motor neurons against hSOD1^G93A-induced apoptosis by activating Xiap. Furthermore, we demonstrate that the neuroprotective impact of DAPK1-knockdown was inhibited by Embelin, an inhibitor of Xiap. These results suggest that modulating the DAPK1/Xiap signaling cascade protects motor neurons from apoptosis, indicating its potential as a therapeutic target in ALS. Significantly, these findings offer new directions for treatment options for ALS patients.

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DAPK1通过调节Xiap/JNK通路诱导hsod1g93a相关肌萎缩性侧索硬化运动神经元凋亡

死亡相关蛋白激酶1 （DAPK1）在调节各种神经退行性疾病的细胞死亡中起关键作用。然而，DAPK1在肌萎缩性侧索硬化症（ALS）发病机制中的作用尚不清楚。这里，我们发现DAPK1在ALS中的表达显著升高，与miR-501-3p呈负相关。上调DAPK1通过抑制Xiap导致运动神经元凋亡增加。相反，DAPK1沉默通过激活Xiap保护运动神经元免受hsod1g93a诱导的凋亡。此外，我们证明了dapk1敲低的神经保护作用被Embelin（一种Xiap抑制剂）所抑制。这些结果表明，调节DAPK1/Xiap信号级联可以保护运动神经元免于凋亡，这表明它可能是ALS的治疗靶点。值得注意的是，这些发现为ALS患者的治疗选择提供了新的方向。

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来源期刊

Molecular and Cellular Neuroscience 医学-神经科学

CiteScore

5.60

自引率

0.00%

发文量

审稿时长

37 days

期刊介绍： Molecular and Cellular Neuroscience publishes original research of high significance covering all aspects of neurosciences indicated by the broadest interpretation of the journal''s title. In particular, the journal focuses on synaptic maintenance, de- and re-organization, neuron-glia communication, and de-/regenerative neurobiology. In addition, studies using animal models of disease with translational prospects and experimental approaches with backward validation of disease signatures from human patients are welcome.