Genentech, Neuroscience, South San Francisco, 94080, USA.
Genentech, Pathology, South San Francisco, 94080, USA.
Sci Rep. 2020 Sep 24;10(1):15713. doi: 10.1038/s41598-020-72723-y.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron loss that ultimately leads to fatal paralysis. Reducing levels or function of the tyrosine kinase, ephrin type-A receptor 4 (EphA4), has been suggested as a potential approach for slowing disease progression in ALS. Because EphA4 plays roles in embryonic nervous system development, study of constitutive knockout (KO) of EphA4 in mice is limited due to confounding phenotypes with homozygous knockout. We used a tamoxifen-inducible EphA4 conditional KO mouse to achieve strong reduction of EphA4 levels in postnatal mice to test for protective effects in the SOD1 model of ALS. We found that EphA4 KO in young mice, but not older adult mice, causes defects in muscle function, consistent with a prolonged postnatal role for EphA4 in adolescent muscle growth. When testing the effects of inducible EphA4 KO at different timepoints in SOD1 mice, we found no benefits on motor function or disease pathology, including muscle denervation and motor neuron loss. Our results demonstrate deleterious effects of reducing EphA4 levels in juvenile mice and do not provide support for the hypothesis that widespread EphA4 reduction is beneficial in the SOD1 mouse model of ALS.
肌萎缩侧索硬化症（ALS）是一种神经退行性疾病，其特征是运动神经元丧失，最终导致致命性瘫痪。降低酪氨酸激酶、Ephrin 型-A 受体 4（EphA4）的水平或功能已被认为是减缓 ALS 疾病进展的一种潜在方法。由于 EphA4 在胚胎神经系统发育中发挥作用，因此由于纯合子敲除的表型混杂，EphA4 组成型敲除（KO）的研究在 EphA4 KO 小鼠中受到限制。我们使用他莫昔芬诱导的 EphA4 条件性 KO 小鼠在出生后小鼠中实现 EphA4 水平的强烈降低，以测试 EphA4 在 ALS 的 SOD1 模型中的保护作用。我们发现 EphA4 KO 在幼鼠中引起肌肉功能缺陷，但在老年成年小鼠中没有，这与 EphA4 在青少年肌肉生长中具有延长的出生后作用一致。当在 SOD1 小鼠中在不同时间点测试诱导 EphA4 KO 的效果时，我们发现运动功能或疾病病理学（包括肌肉去神经支配和运动神经元丧失）没有任何益处。我们的结果表明 EphA4 水平降低在幼年小鼠中具有有害影响，并且不支持 EphA4 广泛减少在 SOD1 小鼠 ALS 模型中有益的假设。
