Amyotrophic lateral sclerosis (ALS) is a devastating motoneuron (Mn) disease without effective cure currently available. Death of MNs in ALS is preceded by failure of neuromuscular junctions and axonal retraction. Neuregulin 1 (NRG1) is a neurotrophic factor highly expressed in MNs and neuromuscular junctions that support axonal and neuromuscular development and maintenance. NRG1 and its ErbB receptors are involved in ALS. Reduced NRG1 expression has been found in ALS patients and in the ALS SOD1G93A mouse model; however, the expression of the isoforms of NRG1 and its receptors is still controversial. Due to the reduced levels of NRG1 type III (NRG1-III) in the spinal cord of ALS patients, we used gene therapy based on intrathecal administration of adeno-associated virus to overexpress NRG1-III in SOD1G93A mice. The mice were evaluated from 9 to 16 weeks of age by electrophysiology and rotarod tests. At 16 weeks, samples were harvested for histological and molecular analyses. Our results indicate that overexpression of NRG1-III is able to preserve neuromuscular function of the hindlimbs, improve locomotor performance, increase the number of surviving MNs, and reduce glial reactivity in the treated female SOD1G93A mice. Furthermore, the NRG1-III/ErbB4 axis appears to regulate MN excitability by modulating the chloride transporter KCC2 and reduces the expression of the MN vulnerability marker MMP-9. However, NRG1-III did not have a significant effect on male mice, indicating relevant sex differences. These findings indicate that increasing NRG1-III at the spinal cord is a promising approach for promoting MN protection and functional improvement in ALS.

中文翻译：

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Neuregulin 1 III 型在 SOD1 相关肌萎缩侧索硬化症中的治疗作用。


肌萎缩侧索硬化症 (ALS) 是一种破坏性的运动神经元 (Mn) 疾病，目前尚无有效治愈方法。 ALS 中的 MN 死亡之前会出现神经肌肉接头衰竭和轴突回缩。神经调节蛋白 1 (NRG1) 是一种神经营养因子，在 MN 和神经肌肉接头中高表达，支持轴突和神经肌肉的发育和维护。 NRG1 及其 ErbB 受体参与 ALS。在 ALS 患者和 ALS SOD1G93A 小鼠模型中发现 NRG1 表达降低；然而，NRG1亚型及其受体的表达仍存在争议。由于ALS患者脊髓中NRG1 III型（NRG1-III）水平降低，我们采用基于鞘内注射腺相关病毒的基因治疗在SOD1G93A小鼠中过度表达NRG1-III。通过电生理学和转棒测试对 9 至 16 周龄的小鼠进行评估。第 16 周时，采集样本进行组织学和分子分析。我们的结果表明，NRG1-III 的过度表达能够保护雌性 SOD1G93A 小鼠后肢的神经肌肉功能，改善运动性能，增加存活的 MN 数量，并减少神经胶质反应性。此外，NRG1-III/ErbB4 轴似乎通过调节氯离子转运蛋白 KCC2 来调节 MN 兴奋性，并减少 MN 脆弱性标记 MMP-9 的表达。然而，NRG1-III 对雄性小鼠没有显着影响，表明存在相关的性别差异。这些发现表明，增加脊髓中的 NRG1-III 是促进 ALS 中 MN 保护和功能改善的一种有前景的方法。