Human motor neuron (MN) diseases encompass a spectrum of disorders. A critical barrier to dissecting disease mechanisms is the lack of appropriate human MN models. Here, we describe a scalable, suspension-based differentiation system to generate functional human MN diseases in 3 weeks. Using this model, we translated recent findings that mRNA mis-localization plays a role in disease development to the human context by establishing a membrane-based system that allows efficient fractionation of MN cell soma and neurites. In response to hypoxia, used to mimic diabetic neuropathies, MNs upregulated mitochondrial transcripts in neurites; however, mitochondria were decreased. These data suggest that hypoxia may disrupt translation of mitochondrial mRNA, potentially leading to neurite damage and development of neuropathies. We report the development of a novel human MN model system to investigate mechanisms of disease affecting soma and/or neurites that facilitates the rapid generation and testing of patient-specific MN diseases.

人类运动神经元（MN）疾病涵盖多种疾病。剖析疾病机制的关键障碍是缺乏合适的人类MN模型。在这里，我们描述了一种可扩展的基于悬浮的分化系统，可在3周内产生功能性人类MN疾病。使用该模型，我们通过建立基于膜的系统来有效分离MN细胞的体细胞和神经突，从而将最近的发现转化为mRNA定位在疾病发展中的作用。在用于模拟糖尿病性神经病的缺氧反应中，MNs上调了神经突中的线粒体转录本。然而，线粒体减少了。这些数据表明缺氧可能会破坏线粒体mRNA的翻译，可能导致神经突损伤和神经病变的发展。