Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China.
Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China.
Neuroscience. 2023 Aug 1;524:65-78. doi: 10.1016/j.neuroscience.2023.05.030. Epub 2023 Jun 7.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease related to the progressive death of motor neurons. Understanding the pathogenesis of ALS continues to provide considerable challenges. Bulbar-onset ALS involves faster functional loss and shorter survival time than spinal cord-onset ALS. However, debate is ongoing regarding typical plasma miRNA changes in ALS patients with bulbar onset. Exosomal miRNAs have not yet been described as a tool for bulbar-onset ALS diagnosis or prognosis prediction. In this study, candidate exosomal miRNAs were identified by small RNA sequencing using samples from patients with bulbar-onset ALS and healthy controls. Potential pathogenic mechanisms were identified through enrichment analysis of target genes for differential miRNAs. Expression of miR-16-5p, miR-23a-3p, miR-22-3p, and miR-93-5p was significantly up-regulated in plasma exosomes from bulbar-onset ALS patients compared with healthy control subjects. Among them, miR-16-5p and miR-23a-3p were significantly lower in spinal-onset ALS patients than those with bulbar-onset. Furthermore, up-regulation of miR-23a-3p in motor neuron-like NSC-34 cells promoted apoptosis and inhibited cell viability. This miRNA was found to directly target ERBB4 and regulate the AKT/GSK3β pathway. Collectively, the above miRNAs and their targets are related to the development of bulbar-onset ALS. Our research indicates that miR-23a-3p might have an effect on motor neuron loss observed in bulbar-onset ALS and may be a novel target for the therapy of ALS in the future.
肌萎缩侧索硬化症（ALS）是一种与运动神经元进行性死亡相关的神经退行性疾病。对 ALS 发病机制的理解仍然存在很大的挑战。延髓起病的 ALS 比脊髓起病的 ALS 更快地丧失功能，存活时间更短。然而，对于延髓起病 ALS 患者的典型血浆 miRNA 变化仍存在争议。外泌体 miRNA 尚未被描述为延髓起病 ALS 诊断或预后预测的工具。在这项研究中，使用延髓起病 ALS 患者和健康对照者的样本，通过小 RNA 测序确定候选外泌体 miRNA。通过对差异 miRNA 的靶基因进行富集分析，确定潜在的致病机制。与健康对照组相比，延髓起病 ALS 患者血浆外泌体中的 miR-16-5p、miR-23a-3p、miR-22-3p 和 miR-93-5p 的表达明显上调。其中，脊髓起病 ALS 患者血浆中的 miR-16-5p 和 miR-23a-3p 明显低于延髓起病患者。此外，运动神经元样 NSC-34 细胞中 miR-23a-3p 的上调促进了细胞凋亡，抑制了细胞活力。发现该 miRNA 直接靶向 ERBB4 并调节 AKT/GSK3β 通路。综上所述，上述 miRNA 及其靶标与延髓起病 ALS 的发展有关。我们的研究表明，miR-23a-3p 可能对延髓起病 ALS 中观察到的运动神经元丢失有影响，可能成为未来 ALS 治疗的新靶点。
