Center for Translational Neuromedicine, University of Copenhagen, Faculty of Health and Medical Sciences, 2200 Copenhagen, Denmark.
Center for Translational Neuromedicine and Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Brain. 2024 Sep 3;147(9):3099-3112. doi: 10.1093/brain/awae166.
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.
亨廷顿病和青少年起病精神分裂症长期以来一直被视为截然不同的疾病。然而，两者均表现出神经胶质分化的内在细胞异常，导致星形胶质细胞功能障碍和少突胶质细胞发育不良。为了评估共同的机制是否可能是这些原本不同的疾病相似的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源自疾病多能干细胞的人类神经胶质祖细胞（hGPC）的 RNA 测序数据。我们在亨廷顿病和精神分裂症 hGPC 之间确定了保留的基因集，而与正常对照不同，该基因集中包含了共享疾病相关网络中的 174 个高度连接的基因，这些基因主要集中在突触信号转导上。这些突触基因在精神分裂症和亨廷顿病 hGPC 中均受到显著抑制，基因调控网络分析确定了该网络的一组核心上游调控因子，其中 OLIG2 和 TCF7L2 较为突出。在它们的下游靶标中，谷氨酸能突触的调节剂 ADGRL3 在精神分裂症和亨廷顿病 hGPC 中均显著受到抑制。染色质免疫沉淀测序证实，OLIG2 和 TCF7L2 各自结合 ADGRL3 的调节区域，而这些转录因子的慢病毒过表达可挽救其表达。这些数据表明，疾病相关的 OLIG2 和 TCF7L2 依赖性谷氨酸信号转导调节因子转录抑制可能会损害神经胶质对神经元谷氨酸的接受能力。随后，hGPC 的活性依赖性动员能力丧失可能导致少突胶质细胞生成不足，从而导致这些疾病中观察到的少突胶质细胞发育不良，以及与每种疾病相关的星形胶质细胞分化和伴随的突触功能障碍。总之，这些数据强调了两种原本无关的疾病，即亨廷顿病和精神分裂症，在发病机制和表型相似性方面的共同神经胶质分子病理学的重要性。
