Kitani-Morii Fukiko, Imamura Keiko, Kondo Takayuki, Ohara Ryo, Enami Takako, Shibukawa Ran, Yamamoto Takuya, Sekiguchi Kazuya, Toguchida Junya, Mizuno Toshiki, Nakagawa Masanori, Inoue Haruhisa
aCenter for iPS Cells for Research and Application (CiRA) bInstitute for Frontier Medical Sciences, Kyoto University cDepartment of Neurology dNorth Medical Center, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Neuroreport. 2017 Sep 6;28(13):814-821. doi: 10.1097/WNR.0000000000000831.
Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy. The majority of CMT is demyelinating type (demyelinating CMT) caused by Schwann cell involvement. Although a large number of genes responsible for demyelinating CMT have been found, the common molecular target of the pathophysiology caused by these different genes in demyelinating CMT is still unknown. We generated induced pluripotent stem cells (iPSCs) from healthy controls and patients with demyelinating CMT caused by duplication in peripheral myelin protein 22 kDa (PMP22) or point mutations in myelin protein zero (MPZ) or early growth response 2 (EGR2). iPSCs were differentiated into neural crest cells, progenitors of Schwann cells, followed by purification using the neural crest cell markers p75 and human natural killer-1. To identify a disease-relevant molecular signature at the early stage of demyelinating CMT, we conducted global gene expression analysis of iPSC-derived neural crest cells and found that a glutathione-mediated detoxification pathway was one of the related pathways in demyelinating CMT. mRNA expression of glutathione S-transferase theta 2 (GSTT2), encoding an important enzyme for glutathione-mediated detoxification, and production of reactive oxygen species were increased in demyelinating CMT. Our study suggested that patient-iPSC-derived neural crest cells could be a cellular model for investigating genetically heterogeneous disease CMT and might provide a therapeutic target for the disease.
夏科-马里-图斯病（CMT）是最常见的遗传性神经病。大多数CMT是由施万细胞受累引起的脱髓鞘型（脱髓鞘性CMT）。尽管已经发现了大量导致脱髓鞘性CMT的基因，但这些不同基因在脱髓鞘性CMT中引起的病理生理学的共同分子靶点仍然未知。我们从健康对照者以及由外周髓鞘蛋白22 kDa（PMP22）重复、髓鞘蛋白零（MPZ）或早期生长反应2（EGR2）点突变导致的脱髓鞘性CMT患者中生成了诱导多能干细胞（iPSC）。iPSC分化为神经嵴细胞，即施万细胞的祖细胞，随后使用神经嵴细胞标志物p75和人类自然杀伤细胞-1进行纯化。为了在脱髓鞘性CMT的早期阶段鉴定与疾病相关的分子特征，我们对iPSC来源的神经嵴细胞进行了全基因组表达分析，发现谷胱甘肽介导的解毒途径是脱髓鞘性CMT中的相关途径之一。在脱髓鞘性CMT中，编码谷胱甘肽介导解毒重要酶的谷胱甘肽S-转移酶θ2（GSTT2）的mRNA表达以及活性氧的产生均增加。我们的研究表明，患者iPSC来源的神经嵴细胞可能是研究基因异质性疾病CMT的细胞模型，并可能为该疾病提供治疗靶点。
