A cellular model for sporadic ALS using patient-derived induced pluripotent stem cells.
A cellular model for sporadic ALS using patient-derived induced pluripotent stem cells.
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DOI：
10.1016/j.mcn.2013.07.007
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发表时间：
2013-09
期刊：
影响因子：
--
通讯作者：
Javaherian A
中科院分区：
文献类型：
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作者：
Burkhardt MF;Martinez FJ;Wright S;Ramos C;Volfson D;Mason M;Garnes J;Dang V;Lievers J;Shoukat-Mumtaz U;Martinez R;Gai H;Blake R;Vaisberg E;Grskovic M;Johnson C;Irion S;Bright J;Cooper B;Nguyen L;Griswold-Prenner I;Javaherian A
遗传复杂的神经退行性疾病，如散发性肌萎缩侧索硬化症（ALS）的治疗方法的发展在很大程度上受到缺乏相关疾病模型的阻碍。将散发性ALS患者的成纤维细胞重编程为诱导多能干细胞（iPSC）并分化为显示疾病表型的受影响神经元可以为疾病机制研究和药物发现提供细胞模型。在这里，我们报告了一个健康对照组和ALS患者的成纤维细胞的多能性重编程及其分化为运动神经元。我们证明，来自三个sALS患者的运动神经元显示从头TDP-43聚集，并且聚集体概括了来自iPSC来源的同一患者之一的死后组织中的病理。我们在下运动神经元和上运动神经元样细胞中使用TDP-43聚集终点配置了高含量的化学筛选，并鉴定了FDA批准的小分子调节剂，包括地高辛，证明了基于患者的iPSC疾病建模用于药物筛选的可行性。
Development of therapeutics for genetically complex neurodegenerative diseases such as sporadic amyotrophic lateral sclerosis (ALS) has largely been hampered by lack of relevant disease models. Reprogramming of sporadic ALS patients’ fibroblasts into induced pluripotent stem cells (iPSC) and differentiation into affected neurons that show a disease phenotype could provide a cellular model for disease mechanism studies and drug discovery. Here we report the reprogramming to pluripotency of fibroblasts from a large cohort of healthy controls and ALS patients and their differentiation into motor neurons. We demonstrate that motor neurons derived from three sALS patients show de novo TDP-43 aggregation and that the aggregates recapitulate pathology in postmortem tissue from one of the same patients from which the iPSC were derived. We configured a high-content chemical screen using the TDP-43 aggregate endpoint both in lower motor neurons and upper motor neuron like cells and identified FDA-approved small molecule modulators including Digoxin demonstrating the feasibility of patient-derived iPSC-based disease modelling for drug screening.