Mitochondrial dysfunction in dopaminergic neurons differentiated from exfoliated deciduous tooth-derived pulp stem cells of a child with Rett syndrome
Mitochondrial dysfunction in dopaminergic neurons differentiated from exfoliated deciduous tooth-derived pulp stem cells of a child with Rett syndrome
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DOI：
10.1016/j.bbrc.2018.03.077
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发表时间：
2018-04-15
影响因子：
3.1
通讯作者：
Nonaka, Kazuaki
中科院分区：
文献类型：
--
作者：
Hirofuji, Saki;Hirofuji, Yuta;Nonaka, Kazuaki
Rett综合征是一种X连锁神经发育障碍，与精神障碍、自主神经功能障碍和自闭症有关。Rett综合征患者在MECP 2（编码甲基CpG结合蛋白2（MeCP 2）的基因）中存在功能缺失突变。在Rett综合征患者中发现了异常的生物胺信号传导和线粒体功能;然而，很少有研究分析这些因素之间的关联。本研究探讨线粒体和神经元分化的MeCP 2缺陷的干细胞从脱落的乳牙Rett综合征的儿童之间的功能关系。本研究中招募的受试者是一名携带大缺失的5岁女孩，该缺失包括MECP 2的甲基-CpG结合结构域、转录抑制结构域和核定位信号。使用单细胞分离技术，我们发现MeCP 2表达和MeCP 2缺陷干细胞的两个群体在体外细胞增殖和神经元分化的整个阶段保持其MECP 2表达谱。在MeCP 2缺陷的多巴胺能神经元中，轴突生长和分支减弱。MeCP 2缺陷细胞显示线粒体膜电位、ATP产生减少，线粒体在神经突中的分布受限，以及中心线粒体分裂因子、动力蛋白相关蛋白1的表达低于MeCP 2表达细胞。这些数据表明，MeCP 2缺陷失调的多巴胺能神经元的成熟所需的线粒体因子的表达。本研究还提供了深入了解发病机制的脑内多巴胺能信号通路功能障碍的Rett综合征。(C)2018爱思唯尔公司All rights reserved.
Rett syndrome is an X-linked neurodevelopmental disorder associated with psychomotor impairments, autonomic dysfunctions and autism. Patients with Rett syndrome have loss-of-function mutations in MECP2, the gene encoding methyl-CpG-binding protein 2 (MeCP2). Abnormal biogenic amine signaling and mitochondrial function have been found in patients with Rett syndrome; however, few studies have analyzed the association between these factors. This study investigated the functional relationships between mitochondria and the neuronal differentiation of the MeCP2-deficient stem cells from the exfoliated deciduous teeth of a child with Rett syndrome. An enrolled subject in this study was a 5-year old girl carrying a large deletion that included the methyl-CpG-binding domain, transcriptional repression domain, and nuclear localization signal of MECP2. Using the single-cell isolation technique, we found that the two populations of MeCP2-expressing and MeCP2-deficient stem cells kept their MECP2 expression profiles throughout the stages of cell proliferation and neuronal differentiation in vitro. Neurite outgrowth and branching were attenuated in MeCP2-deficient dopaminergic neurons. MeCP2-deficient cells showed reduced mitochondria] membrane potential, ATP production, restricted mitochondrial distribution in neurites, and lower expression of a central mitochondrial fission factor, dynamin-related protein 1 than MeCP2-expressing cells. These data indicated that MeCP2-deficiency dysregulates the expression of mitochondrial factors required for the maturation of dopaminergic neurons. This study also provides insight into the pathogenic mechanism underlying dysfunction of the intracerebral dopaminergic signaling pathway in Rett syndrome. (C) 2018 Elsevier Inc. All rights reserved.