Amyotrophic lateral sclerosis (ALS) is an aggressive and uniformly fatal degenerative disease of the motor nervous system. In order to understand underlying disease mechanisms, researchers leverage a host of in vivo and in vitro models, including yeast, worms, flies, zebrafish, mice, and more recently, human induced pluripotent stem cells (iPSCs) derived from ALS patients. While mouse models have been the main workhorse of preclinical ALS research, the development of iPSCs provides a new opportunity to explore molecular phenotypes of ALS within human cells. Importantly, this technology enables modeling of both familial and sporadic ALS in the relevant human genetic backgrounds, as well as a personalized or targeted approach to therapy development. Harnessing these powerful tools requires addressing numerous challenges, including different variance components associated with iPSCs and motor neurons as well as concomitant limits of reductionist approaches. In order to overcome these obstacles, optimization of protocols and assays, confirmation of phenotype robustness at scale, and validation of findings in human tissue and genetics will cement the role for iPSC models as a valuable complement to animal models in ALS and more broadly among neurodegenerative diseases.

中文翻译：

---

使用iPSC对ALS中的细胞自主运动神经元表型进行建模。

肌萎缩性侧索硬化症（ALS）是运动神经系统的一种侵略性且致命性的退化性疾病。为了了解潜在的疾病机制，研究人员利用了许多体内和体外模型，包括酵母，蠕虫，苍蝇，斑马鱼，小鼠，以及最近来自人ALS患者的人诱导多能干细胞（iPSC）。尽管小鼠模型一直是临床前ALS研究的主要力量，但iPSC的发展为探索人细胞内ALS的分子表型提供了新的机会。重要的是，这项技术可以在相关的人类遗传背景下对家族性和散发性ALS进行建模，以及个性化或针对性的疗法开发方法。利用这些强大的工具需要应对众多挑战，包括与iPSC和运动神经元相关的不同方差成分，以及归约方法的局限性。为了克服这些障碍，优化方案和测定方法，大规模确定表型的稳健性以及验证人类组织和遗传学方面的发现将巩固iPSC模型的作用，作为ALS中动物模型的宝贵补充，并且在神经退行性疾病中更广泛地发挥作用疾病。