MeCP2 突变对 Rett 综合征患者衍生人脑器官组织功能网络的早期不同影响

Tatsuya Osaki, Chloe Delepine, Yuma Osako, Devorah Kranz, April R Levin, Charles Nelson, Michela Fagiolini, Mriganka Sur
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引用次数: 0

摘要

从诱导多能干细胞中提取的人脑器官组织能重现早期发育过程,并揭示涉及神经发育障碍的变化。X连锁甲基CpG结合蛋白2(MECP2)基因突变与Rett综合征有关,疾病的严重程度因突变的位置和类型而异。在这里,我们利用三光子显微镜的钙成像技术分析了两种类型的 MeCP2 突变,一种是错义突变(R306C),另一种是截断突变(V247X)。与同源对照组相比,我们发现Rett器官组织中的神经元活动异常,而且基于图论分析的网络功能也发生了改变,V247X突变对功能反应和连接性的影响比R306C突变更严重。这些变化与从具有类似突变的患者身上获得的脑电图数据一致。标记 DLX 启动子驱动的抑制性神经元表明,两种突变类型的抑制性神经元和兴奋性神经元在活动和功能连接性方面存在差异。转录组分析显示,在R306C器官组织中,HDAC2相关性受损,而在V247X器官组织中,兴奋性神经元的GABAA受体表达减少。这些发现证明了Rett综合征易感性的突变特异性机制,并提出了有针对性的治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Early differential impact of MeCP2 mutations on functional networks in Rett syndrome patient-derived human cerebral organoids
Human cerebral organoids derived from induced pluripotent stem cells can recapture early developmental processes and reveal changes involving neurodevelopmental disorders. Mutations in the X linked methyl CpG binding protein 2 (MECP2) gene are associated with Rett syndrome, and disease severity varies depending on the location and type of mutation. Here, we focused on neuronal activity in Rett syndrome patient-derived organoids, analyzing two types of MeCP2 mutations a missense mutation (R306C) and a truncating mutation (V247X) using calcium imaging with three-photon microscopy. Compared to isogenic controls, we found abnormal neuronal activity in Rett organoids and altered network function based on graph theoretic analyses, with V247X mutations impacting functional responses and connectivity more severely than R306C mutations. These changes paralleled EEG data obtained from patients with comparable mutations. Labeling DLX promoter-driven inhibitory neurons demonstrated differences in activity and functional connectivity of inhibitory and excitatory neurons in the two types of mutation. Transcriptomic analyses revealed HDAC2-associated impairment in R306C organoids and decreased GABAA receptor expression in excitatory neurons in V247X organoids. These findings demonstrate mutation-specific mechanisms of vulnerability in Rett syndrome and suggest targeted strategies for their treatment.
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