Mutations in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS). Accumulating evidence implicates astrocytes as important non-cell autonomous contributors to ALS pathogenesis, although the potential deleterious effects of astrocytes on the function of motor neurons remains to be determined in a completely humanized model of C9orf72-mediated ALS. Here, we use a human iPSC-based model to study the cell autonomous and non-autonomous consequences of mutant C9orf72 expression by astrocytes. We show that mutant astrocytes both recapitulate key aspects of C9orf72-related ALS pathology and, upon co-culture, cause motor neurons to undergo a progressive loss of action potential output due to decreases in the magnitude of voltage-activated Na+ and K+ currents. Importantly, CRISPR/Cas-9 mediated excision of the C9orf72 repeat expansion reverses these phenotypes, confirming that the C9orf72 mutation is responsible for both cell-autonomous astrocyte pathology and non-cell autonomous motor neuron pathophysiology.

中文翻译：

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突变的C9orf72人iPSC来源的星形胶质细胞引起非细胞自主运动神经元病理生理。

C9orf72中的突变是肌萎缩性侧索硬化症（ALS）的最常见遗传原因。越来越多的证据表明，星形胶质细胞是ALS发病机制的重要非细胞自主贡献者，尽管在C9orf72介导的ALS的完全人源化模型中，星形胶质细胞对运动神经元功能的潜在有害作用仍有待确定。在这里，我们使用基于人类iPSC的模型来研究星形胶质细胞突变C9orf72表达的细胞自主和非自主后果。我们显示突变的星形胶质细胞既概括了C9orf72相关ALS病理学的关键方面，又在共培养后，由于电压激活的Na +和K +电流的大小降低，导致运动神经元经历动作电位输出的逐渐丧失。重要的，