REST and Neural Gene Network Dysregulation in iPSC Models of Alzheimer's Disease
REST and Neural Gene Network Dysregulation in iPSC Models of Alzheimer's Disease
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DOI：
10.1016/j.celrep.2019.01.023
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发表时间：
2019-01-29
期刊：
影响因子：
8.8
通讯作者：
Yankner, Bruce A.
中科院分区：
文献类型：
--
作者：
Meyer, Katharina;Feldman, Heather M.;Yankner, Bruce A.
导致阿尔茨海默病（AD）的最早期神经元变化的分子基础尚不清楚。在这里，我们分析了来自散发性AD（SAD），APOE 4基因编辑和对照诱导多能干细胞（iPSC）的神经细胞。我们观察到iPSC衍生的神经祖细胞（NP）细胞和神经元在与神经元分化，神经发生和突触传递相关的基因网络中的主要差异。来自SAD患者的iPSC衍生的神经细胞表现出加速的神经分化和减少的祖细胞更新。此外，类似的表型出现在NP细胞和源自APOE4 iPSC的脑类器官中。转录抑制因子REST的功能受损与转录组和分化状态的改变密切相关。SAD和APOE4表达导致REST核转位和染色质结合减少，以及核纤层破坏。因此，神经基因网络的失调可能启动导致AD的病理级联反应。
The molecular basis of the earliest neuronal changes that lead to Alzheimer's disease (AD) is unclear. Here, we analyze neural cells derived from sporadic AD (SAD), APOE4 gene-edited and control induced pluripotent stem cells (iPSCs). We observe major differences in iPSC-derived neural progenitor (NP) cells and neurons in gene networks related to neuronal differentiation, neurogenesis, and synaptic transmission. The iPSC-derived neural cells from SAD patients exhibit accelerated neural differentiation and reduced progenitor cell renewal. Moreover, a similar phenotype appears in NP cells and cerebral organoids derived from APOE4 iPSCs. Impaired function of the transcriptional repressor REST is strongly implicated in the altered transcriptome and differentiation state. SAD and APOE4 expression result in reduced REST nuclear translocation and chromatin binding, and disruption of the nuclear lamina. Thus, dysregulation of neural gene networks may set in motion the pathologic cascade that leads to AD.