Graduate Schools of Medical Science and Engineering, KAIST, 291 Daehak-ro, Yuseong-gu, Daejeon 305-701, Republic of Korea.
Department of Biological Sciences, KAIST, 291 Daehak-ro, Yuseong-gu, Daejeon 305-701, Republic of Korea.
Biochem Biophys Res Commun. 2014 Feb 14;444(3):311-8. doi: 10.1016/j.bbrc.2014.01.038. Epub 2014 Jan 24.
Menkes disease (MD) is a copper-deficient neurodegenerative disorder that manifests severe neurologic symptoms such as seizures, lethargic states, and hypotonia. Menkes disease is due to a dysfunction of ATP7A, but the pathophysiology of neurologic manifestation is poorly understood during embryonic development. To understand the pathophysiology of neurologic symptoms, molecular and cellular phenotypes were investigated in Menkes disease-derived induced pluripotent stem cells (MD-iPSCs). MD-iPSCs were generated from fibroblasts of a Menkes disease patient. Abnormal reticular distribution of ATP7A was observed in MD-fibroblasts and MD-iPSCs, respectively. MD-iPSCs showed abnormal morphology in appearance during embryoid body (EB) formation as compared with wild type (WT)-iPSCs. Intriguingly, aberrant switch of E-cadherin (E-cad) to N-cadherin (N-cad) and impaired neural rosette formation were shown in MD-iPSCs during early differentiation. When extracellular copper was chelated in WT-iPSCs by treatment with bathocuprione sulfate, aberrant switch of E-cad to N-cad and impaired neuronal differentiation were observed, like in MD-iPSCs. Our results suggest that neurological defects in Menkes disease patients may be responsible for aberrant cadherin transition and impaired neuronal differentiation during early developmental stage.
Menkes 病（MD）是一种铜缺乏性神经退行性疾病，表现为严重的神经症状，如癫痫、昏睡状态和低张力。Menkes 病是由于 ATP7A 功能障碍引起的，但在胚胎发育过程中，其神经表现的病理生理学仍知之甚少。为了了解神经症状的病理生理学，我们在 Menkes 病衍生的诱导多能干细胞（MD-iPSCs）中研究了分子和细胞表型。MD-iPSCs 是从 Menkes 病患者的成纤维细胞中产生的。在 MD 成纤维细胞和 MD-iPSCs 中分别观察到 ATP7A 的异常网状分布。与野生型（WT）-iPSCs 相比，MD-iPSCs 在类胚体（EB）形成过程中表现出异常的形态。有趣的是，在早期分化过程中，MD-iPSCs 表现出 E-钙粘蛋白（E-cad）向 N-钙粘蛋白（N-cad）的异常转换和神经玫瑰花结形成受损。当用硫酸 bathocuprione 将 WT-iPSCs 中的细胞外铜螯合时，观察到 E-cad 向 N-cad 的异常转换和神经元分化受损，与 MD-iPSCs 相似。我们的研究结果表明，Menkes 病患者的神经缺陷可能与早期发育阶段的异常钙粘蛋白转换和神经元分化受损有关。
