RBM5 induces motor neuron apoptosis in hSOD1G93A-related amyotrophic lateral sclerosis by inhibiting Rac1/AKT pathways

IF 3.5 3区 医学 Q2 NEUROSCIENCES Brain Research Bulletin Pub Date : 2024-08-12 DOI:10.1016/j.brainresbull.2024.111049
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Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder distinguished by gradual depletion of motor neurons. RNA binding motif protein 5 (RBM5), an abundantly expressed RNA-binding protein, plays a critical role in the process of cellular death. However, little is known about the role of RBM5 in the pathogenesis of ALS. Here, we found that RBM5 was upregulated in ALS hSOD1G93A-NSC34 cell models and hSOD1G93A mice due to a reduction of miR-141–5p. The upregulation of RBM5 increased the apoptosis of motor neurons by inhibiting Rac1-mediated neuroprotection. In contrast, genetic knockdown of RBM5 rescued motor neurons from hSOD1G93A-induced degeneration by activating Rac1 signaling. The neuroprotective effect of RBM5-knockdown was significantly inhibited by the Rac1 inhibitor, NSC23766. These findings suggest that RBM5 could potentially serve as a therapeutic target in ALS by activating the Rac1 signalling.

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RBM5 通过抑制 Rac1/AKT 通路诱导 hSOD1G93A 相关肌萎缩性脊髓侧索硬化症的运动神经元凋亡。
肌萎缩性脊髓侧索硬化症(ALS)是一种致命的神经退行性疾病,表现为运动神经元的逐渐衰竭。RNA 结合基调蛋白 5(RBM5)是一种大量表达的 RNA 结合蛋白,在细胞死亡过程中起着至关重要的作用。然而,人们对 RBM5 在 ALS 发病机制中的作用知之甚少。在这里,我们发现由于 miR-141-5p 的减少,RBM5 在 ALS hSOD1G93A-NSC34 细胞模型和 hSOD1G93A 小鼠中上调。RBM5 的上调抑制了 Rac1 介导的神经保护作用,从而增加了运动神经元的凋亡。与此相反,基因敲除 RBM5 可通过激活 Rac1 信号转导来挽救运动神经元,使其免于 hSOD1G93A 诱导的变性。Rac1 抑制剂 NSC23766 显著抑制了 RBM5 基因敲除的神经保护作用。这些发现表明,RBM5 有可能通过激活 Rac1 信号成为 ALS 的治疗靶点。
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来源期刊
Brain Research Bulletin
Brain Research Bulletin 医学-神经科学
CiteScore
6.90
自引率
2.60%
发文量
253
审稿时长
67 days
期刊介绍: The Brain Research Bulletin (BRB) aims to publish novel work that advances our knowledge of molecular and cellular mechanisms that underlie neural network properties associated with behavior, cognition and other brain functions during neurodevelopment and in the adult. Although clinical research is out of the Journal''s scope, the BRB also aims to publish translation research that provides insight into biological mechanisms and processes associated with neurodegeneration mechanisms, neurological diseases and neuropsychiatric disorders. The Journal is especially interested in research using novel methodologies, such as optogenetics, multielectrode array recordings and life imaging in wild-type and genetically-modified animal models, with the goal to advance our understanding of how neurons, glia and networks function in vivo.
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