PDF(Pubmed)
Abstract：
Huntington\'s disease and juvenile-onset schizophrenia have long been regarded as distinct disorders. However, both manifest cell-intrinsic abnormalities in glial differentiation, with resultant astrocytic dysfunction and hypomyelination. To assess whether a common mechanism might underlie the similar glial pathology of these otherwise disparate conditions, we used comparative correlation network approaches to analyse RNA-sequencing data from human glial progenitor cells (hGPCs) produced from disease-derived pluripotent stem cells. We identified gene sets preserved between Huntington\'s disease and schizophrenia hGPCs yet distinct from normal controls that included 174 highly connected genes in the shared disease-associated network, focusing on genes involved in synaptic signalling. These synaptic genes were largely suppressed in both schizophrenia and Huntington\'s disease hGPCs, and gene regulatory network analysis identified a core set of upstream regulators of this network, of which OLIG2 and TCF7L2 were prominent. Among their downstream targets, ADGRL3, a modulator of glutamatergic synapses, was notably suppressed in both schizophrenia and Huntington\'s disease hGPCs. Chromatin immunoprecipitation sequencing confirmed that OLIG2 and TCF7L2 each bound to the regulatory region of ADGRL3, whose expression was then rescued by lentiviral overexpression of these transcription factors. These data suggest that the disease-associated suppression of OLIG2 and TCF7L2-dependent transcription of glutamate signalling regulators may impair glial receptivity to neuronal glutamate. The consequent loss of activity-dependent mobilization of hGPCs may yield deficient oligodendrocyte production, and hence the hypomyelination noted in these disorders, as well as the disrupted astrocytic differentiation and attendant synaptic dysfunction associated with each. Together, these data highlight the importance of convergent glial molecular pathology in both the pathogenesis and phenotypic similarities of two otherwise unrelated disorders, Huntington\'s disease and schizophrenia.
摘要：
亨廷顿病和青少年精神分裂症长期以来被认为是不同的疾病。然而,两者都在神经胶质分化中表现出细胞内在异常，导致星形细胞功能障碍和髓鞘减少。为了评估一种共同的机制是否可能是这些不同条件的类似神经胶质病理学的基础，我们使用比较相关网络方法分析了由疾病来源的多能干细胞产生的人神经胶质祖细胞(hGPCs)的RNA测序数据.我们确定了亨廷顿氏病和精神分裂症hGPCs之间保留的基因集，但与正常对照不同，正常对照在共享疾病相关网络中包括174个高度连接的基因。专注于参与突触信号传导的基因。这些突触基因在精神分裂症和亨廷顿病hGPCs中都受到抑制，基因调控网络分析确定了该网络的一组核心上游调控者，其中OLIG2和TCF7L2突出。在他们的下游目标中，ADGRL3，谷氨酸能突触的调节剂，在精神分裂症和亨廷顿氏病hGPCs中均受到明显抑制。染色质免疫沉淀测序证实OLIG2和TCF7L2各自与ADGRL3的调节区结合，然后通过这些转录因子的慢病毒过表达来挽救其表达。这些数据表明，与OLIG2和TCF7L2相关的谷氨酸信号调节因子转录的疾病相关抑制可能会损害神经胶质对神经元谷氨酸的接受性。因此，hGPCs的活性依赖性动员的丧失可能会导致少突胶质细胞产生不足，因此，在这些疾病中注意到了髓鞘减少，以及与之相关的星形胶质细胞分化中断和随之而来的突触功能障碍。一起,这些数据强调了趋同神经胶质分子病理学在两种不相关疾病的发病机制和表型相似性中的重要性。亨廷顿病和精神分裂症。
