Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
Queensland Institute of Medical Research, Brisbane, Queensland, Australia.
Sci Rep. 2018 Jul 30;8(1):11393. doi: 10.1038/s41598-018-29845-1.
Amyotrophic lateral sclerosis (ALS) is an untreatable, progressive, neurodegenerative disease specifically affecting motor neurons. Recently, the tyrosine kinase receptor EphA4 was directly implicated in ALS disease progression. We report that a long-lived mutated form of the EphA4 antagonist EphA4-Fc (mutEphA4-Fc), which blocks EphA4 binding to its ligands and inhibits its function, significantly improved functional performance in SOD1 ALS model mice, as assessed by rotarod and hind-limb grip strength tests. Further, heterozygous motor neuron-specific EphA4 gene deletion in SOD1 mice promoted significant improvement in functional performance during the disease course and a delay in disease onset relative to control mice. Importantly, mice in the heterozygous deletion group showed significantly improved survival of motor neurons and architecture of endplates of neuromuscular junctions compared with control and homozygous EphA4-deletion groups. Our novel results show that EphA4 signalling directly regulates motor neuron survival and that mutEphA4-Fc is a promising therapeutic candidate to slow disease progression in ALS.
肌萎缩侧索硬化症（ALS）是一种无法治愈的进行性神经退行性疾病，特别影响运动神经元。最近，酪氨酸激酶受体 EphA4 被直接牵连到 ALS 疾病的进展中。我们报告说，一种长寿命的 EphA4 拮抗剂 EphA4-Fc 的突变形式（mutEphA4-Fc），它可以阻断 EphA4 与其配体的结合并抑制其功能，在 SOD1 ALS 模型小鼠中显著改善了功能表现，通过转棒和后肢抓握强度测试进行评估。此外，SOD1 小鼠中的杂合运动神经元特异性 EphA4 基因缺失促进了疾病过程中功能表现的显著改善，并与对照小鼠相比延迟了疾病发作。重要的是，与对照和 EphA4 基因缺失纯合子组相比，杂合缺失组的小鼠显示出运动神经元的存活率和神经肌肉接头终板结构的显著改善。我们的新结果表明，EphA4 信号直接调节运动神经元的存活，并且 mutEphA4-Fc 是一种有前途的治疗候选药物，可以减缓 ALS 的疾病进展。
