Progressive Motor Neuron Pathology and the Role of Astrocytes in a Human Stem Cell Model of VCP-Related ALS.
Progressive Motor Neuron Pathology and the Role of Astrocytes in a Human Stem Cell Model of VCP-Related ALS.
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DOI：
10.1016/j.celrep.2017.05.024
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发表时间：
2017-05-30
期刊：
影响因子：
8.8
通讯作者：
Patani R
中科院分区：
文献类型：
--
作者：
Hall CE;Yao Z;Choi M;Tyzack GE;Serio A;Luisier R;Harley J;Preza E;Arber C;Crisp SJ;Watson PMD;Kullmann DM;Abramov AY;Wray S;Burley R;Loh SHY;Martins LM;Stevens MM;Luscombe NM;Sibley CR;Lakatos A;Ule J;Gandhi S;Patani R
运动神经元（MN）和星形胶质细胞（AC）参与肌萎缩侧索硬化症（ALS）的发病机制，但它们之间的相互作用和导致MN死亡的分子事件序列仍未得到解决。在这里，我们优化了诱导多能干细胞（iPSC）定向分化为高度富集（> 85%）的脊髓MN和AC的功能群体。我们确定显著增加的细胞质TDP-43和ER应激是患者特异性含缬氨肽蛋白（VCP）突变MN的主要致病事件，伴有继发性线粒体功能障碍和氧化应激。累积起来，这些细胞应激导致VCP突变MN中的突触病理学和细胞死亡。我们还确定了一个细胞自主VCP突变AC生存表型，这是不属于VCP突变MN中发生的相同的分子病理。最后，通过迭代共培养实验，我们发现非细胞自主的VCP突变AC控制和突变MN的影响。这项工作阐明了分子事件和细胞的相互作用，可以指导未来的治疗策略在ALS。来自人iPSCs的VCP突变型运动神经元的稳健且富集的运动神经发生和星形胶质细胞发生显示TDP-43错误定位和ER应激，因为早期致病事件VCP突变型星形胶质细胞表现出细胞自主存活表型VCP突变扰乱星形胶质细胞支持运动神经元存活的能力Hall et al.使用iPSCs来检查运动神经元在ALS的遗传形式中退化的事件序列。他们发现，星形胶质细胞，一种支持细胞，也在这些条件下退化。导致ALS的突变破坏了星形胶质细胞促进运动神经元存活的能力。
Motor neurons (MNs) and astrocytes (ACs) are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), but their interaction and the sequence of molecular events leading to MN death remain unresolved. Here, we optimized directed differentiation of induced pluripotent stem cells (iPSCs) into highly enriched (> 85%) functional populations of spinal cord MNs and ACs. We identify significantly increased cytoplasmic TDP-43 and ER stress as primary pathogenic events in patient-specific valosin-containing protein (VCP)-mutant MNs, with secondary mitochondrial dysfunction and oxidative stress. Cumulatively, these cellular stresses result in synaptic pathology and cell death in VCP-mutant MNs. We additionally identify a cell-autonomous VCP-mutant AC survival phenotype, which is not attributable to the same molecular pathology occurring in VCP-mutant MNs. Finally, through iterative co-culture experiments, we uncover non-cell-autonomous effects of VCP-mutant ACs on both control and mutant MNs. This work elucidates molecular events and cellular interplay that could guide future therapeutic strategies in ALS. Robust and enriched motor neurogenesis and astrogliogenesis from human iPSCs VCP-mutant motor neurons show TDP-43 mislocalization and ER stress as early pathogenic events VCP-mutant astrocytes exhibit a cell-autonomous survival phenotype VCP-mutations perturb the ability of astrocytes to support motor neuron survival Hall et al. use iPSCs to examine the sequence of events by which motor neurons degenerate in a genetic form of ALS. They find that astrocytes, a type of supportive cell, also degenerate under these conditions. The ALS-causing mutation disrupts the ability of astrocytes to promote survival of motor neurons.