Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK; UK Dementia Research Institute, University College London, London WC1E 6BT, UK.
Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, UK.
Cell Rep. 2020 Mar 17;30(11):3655-3662.e2. doi: 10.1016/j.celrep.2020.02.078.
Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease resulting from a complex interplay between genetics and environment. Impairments in axonal transport have been identified in several ALS models, but in vivo evidence remains limited, thus their pathogenetic importance remains to be fully resolved. We therefore analyzed the in vivo dynamics of retrogradely transported, neurotrophin-containing signaling endosomes in nerve axons of two ALS mouse models with mutations in the RNA processing genes TARDBP and FUS. TDP-43 mice, which show neuromuscular pathology without motor neuron loss, display axonal transport perturbations manifesting between 1.5 and 3 months and preceding symptom onset. Contrastingly, despite 20% motor neuron loss, transport remained largely unaffected in Fus mice. Deficiencies in retrograde axonal transport of signaling endosomes are therefore not shared by all ALS-linked genes, indicating that there are mechanistic distinctions in the pathogenesis of ALS caused by mutations in different RNA processing genes.
肌萎缩侧索硬化症（ALS）是一种致命的、进行性的神经退行性疾病，由遗传和环境之间的复杂相互作用引起。在几种 ALS 模型中已经发现了轴突运输的损伤，但体内证据仍然有限，因此其发病机制的重要性仍有待完全解决。因此，我们分析了 RNA 处理基因 TARDBP 和 FUS 突变的两种 ALS 小鼠模型中神经轴突中逆行运输的含有神经营养因子的信号内体的体内动力学。TDP-43 小鼠表现出神经肌肉病理学而没有运动神经元丧失，显示出 1.5 到 3 个月之间出现的轴突运输扰动，并在症状出现之前出现。相比之下，尽管有 20%的运动神经元丧失，但 Fus 小鼠的运输仍然基本不受影响。因此，信号内体的逆行轴突运输缺陷并非所有与 ALS 相关的基因所共有，这表明由不同 RNA 处理基因突变引起的 ALS 的发病机制存在机制上的差异。
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