Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, which is still missing effective therapeutic strategies. Although manipulation of neuronal excitability has been tested in murine and human ALS models, it is still under debate whether neuronal activity might represent a valid target for efficient therapies. In this study, we exploited a combination of transcriptomics, proteomics, optogenetics and pharmacological approaches to investigate the activity-related pathological features of iPSC-derived C9orf72-mutant motoneurons (MN). We found that human ALS^C9orf72 MN are characterized by accumulation of aberrant aggresomes, reduced expression of synaptic genes, loss of synaptic contacts and a dynamic “malactivation” of the transcription factor CREB. A similar phenotype was also found in TBK1-mutant MN and upon overexpression of poly(GA) aggregates in primary neurons, indicating a strong convergence of pathological phenotypes on synaptic dysregulation. Notably, these alterations, along with neuronal survival, could be rescued by treating ALS-related neurons with the K⁺ channel blockers Apamin and XE991, which, respectively, target the SK and the Kv7 channels. Thus, our study shows that restoring the activity-dependent transcriptional programme and synaptic composition exerts a neuroprotective effect on ALS disease progression.

中文翻译：

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ALS 中 K+ 通道阻滞剂可恢复突触破坏和 CREB ​​调节的转录

肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，目前仍缺乏有效的治疗策略。尽管神经元兴奋性的操纵已经在小鼠和人类 ALS 模型中进行了测试，但神经元活动是否可能代表有效治疗的有效目标仍存在争议。在这项研究中，我们综合运用转录组学、蛋白质组学、光遗传学和药理学方法来研究 iPSC 衍生的 C9orf72 突变运动神经元 (MN) 的活动相关病理特征。我们发现人类 ALS ^C9orf72 MN 的特征是异常聚集体的积累、突触基因表达减少、突触接触丧失以及转录因子 CREB ​​的动态“失活”。在 TBK1 突变型 MN 中以及原代神经元中聚 GA 聚集体过度表达时也发现了类似的表型，表明突触失调的病理表型有很强的趋同性。值得注意的是，这些改变以及神经元存活可以通过用 K ⁺通道阻滞剂 Apamin 和 XE991 治疗 ALS 相关神经元来挽救，这两种药物分别针对 SK 和 Kv7 通道。因此，我们的研究表明，恢复活性依赖性转录程序和突触组成对 ALS 疾病进展具有神经保护作用。