Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting motoneurons (MNs), with no effective treatment currently available. The molecular mechanisms that are involved in MN death are complex and not fully understood, with partial contributions of surrounding glial cells and skeletal muscle to the disease. Neuregulin 1 (NRG1) is a trophic factor highly expressed in MNs and neuromuscular junctions. Recent studies have suggested a crucial role of the isoform I (NRG1-I) in the collateral reinnervation process in skeletal muscle, and NRG1-III in the preservation of MNs in the spinal cord, opening a window for developing novel therapies for neuromuscular diseases like ALS. In this study, we overexpressed NRG1-I widely in the skeletal muscles of the SOD1G93A transgenic mouse. The results show that NRG1 gene therapy activated the survival pathways in muscle and spinal cord, increasing the number of surviving MNs and neuromuscular junctions and reducing the astroglial reactivity in the spinal cord of the treated SOD1G93A mice. Furthermore, NRG1-I overexpression preserved motor function and delayed the onset of clinical disease. In summary, our data indicates that NRG1 plays an important role on MN survival and muscle innervation in ALS, and that viral-mediated overexpression of NRG1 isoforms may be considered as a promising approach for ALS treatment.

中文翻译：

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在骨骼肌中过度表达神经调节蛋白1型的基因治疗可促进SOD1G93A ALS小鼠的功能改善。

肌萎缩性侧索硬化症（ALS）是一种影响运动神经元（MN）的神经退行性疾病，目前尚无有效的治疗方法。MN死亡涉及的分子机制是复杂的，尚未完全了解，周围神经胶质细胞和骨骼肌对疾病的部分贡献。神经调节蛋白1（NRG1）是在MN和神经肌肉接头中高表达的营养因子。最近的研究表明，同工型I（NRG1-I）在骨骼肌侧神经支配过程中起着至关重要的作用，而NRG1-III在脊髓中MN的保存中起着重要的作用，为开发新的神经肌肉疾病疗法（例如ALS。在这项研究中，我们在SOD1G93A转基因小鼠的骨骼肌中广泛表达了NRG1-I。结果表明，NRG1基因疗法激活了肌肉和脊髓的存活途径，增加了存活的MN和神经肌肉接头的数量，并降低了SOD1G93A小鼠脊髓的星形胶质反应性。此外，NRG1-I的过表达保留了运动功能并延迟了临床疾病的发作。总之，我们的数据表明NRG1在ALS的MN生存和肌肉神经支配中起着重要作用，并且病毒介导的NRG1亚型的过表达可能被认为是ALS治疗的有前途的方法。NRG1-I的过表达保留了运动功能并延迟了临床疾病的发作。总之，我们的数据表明NRG1在ALS的MN生存和肌肉神经支配中起着重要作用，并且病毒介导的NRG1亚型的过表达可能被认为是ALS治疗的有前途的方法。NRG1-I的过表达保留了运动功能并延迟了临床疾病的发作。总之，我们的数据表明NRG1在ALS的MN生存和肌肉神经支配中起着重要作用，并且病毒介导的NRG1亚型的过表达可能被认为是ALS治疗的有前途的方法。