Department of Neurology, Sean M. Healey & AMG Center for ALS, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Department of Neurology, Sean M. Healey & AMG Center for ALS, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; The Collaborative Center for X-Linked Dystonia-Parkinsonism, Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Cell Rep. 2023 Sep 26;42(9):113046. doi: 10.1016/j.celrep.2023.113046. Epub 2023 Aug 30.
Motor neuron degeneration, the defining feature of amyotrophic lateral sclerosis (ALS), is a primary example of cell-type specificity in neurodegenerative diseases. Using isogenic pairs of induced pluripotent stem cells (iPSCs) harboring different familial ALS mutations, we assess the capacity of iPSC-derived lower motor neurons, sensory neurons, astrocytes, and superficial cortical neurons to capture disease features including transcriptional and splicing dysregulation observed in human postmortem neurons. At early time points, differentially regulated genes in iPSC-derived lower motor neurons, but not other cell types, overlap with one-third of the differentially regulated genes in laser-dissected motor neurons from ALS compared with control postmortem spinal cords. For genes altered in both the iPSC model and bona fide human lower motor neurons, expression changes correlate between the two populations. In iPSC-derived lower motor neurons, but not other derived cell types, we detect the downregulation of genes affected by TDP-43-dependent splicing. This reduction takes place exclusively within genotypes known to involve TDP-43 pathology.
运动神经元退化是肌萎缩侧索硬化症（ALS）的特征，是神经退行性疾病中细胞类型特异性的主要例子。使用携带不同家族性 ALS 突变的同源诱导多能干细胞（iPSC）对，我们评估了 iPSC 衍生的下运动神经元、感觉神经元、星形胶质细胞和浅层皮质神经元捕获疾病特征的能力，包括在人类死后神经元中观察到的转录和剪接失调。在早期，iPSC 衍生的下运动神经元中差异调节的基因，而不是其他细胞类型，与从 ALS 与对照死后脊髓相比，激光切割运动神经元中差异调节的基因的三分之一重叠。对于在 iPSC 模型和真正的人类下运动神经元中都改变的基因，两个群体之间的表达变化相关。在 iPSC 衍生的下运动神经元中，但不是其他衍生的细胞类型中，我们检测到受 TDP-43 依赖性剪接影响的基因下调。这种减少仅发生在已知涉及 TDP-43 病理学的基因型中。
