Pathways disrupted in human ALS motor neurons identified through genetic correction of mutant SOD1.
Pathways disrupted in human ALS motor neurons identified through genetic correction of mutant SOD1.
复制标题
通过突变SOD1的遗传校正确定的人ALS运动神经元中破坏的途径。
DOI：
10.1016/j.stem.2014.03.004
复制
发表时间：
2014-06-05
期刊：
影响因子：
23.9
通讯作者：
Eggan K
中科院分区：
文献类型：
--
作者：
Kiskinis E;Sandoe J;Williams LA;Boulting GL;Moccia R;Wainger BJ;Han S;Peng T;Thams S;Mikkilineni S;Mellin C;Merkle FT;Davis-Dusenbery BN;Ziller M;Oakley D;Ichida J;Di Costanzo S;Atwater N;Maeder ML;Goodwin MJ;Nemesh J;Handsaker RE;Paull D;Noggle S;McCarroll SA;Joung JK;Woolf CJ;Brown RH;Eggan K
虽然已知多种基因中的许多不同突变会导致肌萎缩侧索硬化症（ALS），但对它们如何选择性地影响运动神经元生物学以及它们是否会聚在共同途径上导致神经元变性仍然知之甚少。在这里，我们结合了重编程和干细胞分化的方法与基因组工程和RNA测序，以确定转录和功能的变化，在人类运动神经元中诱导的突变SOD 1。突变体SOD 1蛋白诱导的转录特征指示增加的氧化应激，降低线粒体功能，改变亚细胞转运以及ER应激和未折叠蛋白反应途径的激活。功能研究表明，这些途径受到干扰的方式依赖于SOD1突变。最后，询问从ALS患者产生的干细胞衍生的运动神经元，其在C9orf72中具有重复扩增，表明这些变化中至少有一个子集在ALS中更广泛地保守。
Although many distinct mutations in a variety of genes are known to cause Amyotrophic Lateral Sclerosis (ALS), it remains poorly understood how they selectively impact motor neuron biology and whether they converge on common pathways to cause neuronal degeneration. Here, we have combined reprogramming and stem cell differentiation approaches with genome engineering and RNA sequencing to define the transcriptional and functional changes that are induced in human motor neurons by mutant SOD1. Mutant SOD1 protein induced a transcriptional signature indicative of increased oxidative stress, reduced mitochondrial function, altered sub-cellular transport as well as activation of the ER stress and unfolded protein response pathways. Functional studies demonstrated that these pathways were perturbed in a manner dependent on the SOD1 mutation. Finally, interrogation of stem cell-derived motor neurons produced from ALS patients harboring a repeat expansion in C9orf72 indicates at least a subset of these changes are more broadly conserved in ALS.