Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney, 2139 NSW, Australia
Sydney Medical School, University of Sydney, Sydney, 2050 NSW, Australia.
Dis Model Mech. 2020 Jan 13;13(2):dmm041541. doi: 10.1242/dmm.041541.
encodes a copper-transporting P-type ATPase and is one of 23 genes in which mutations produce distal hereditary motor neuropathy (dHMN), a group of diseases characterized by length-dependent axonal degeneration of motor neurons. We have generated induced pluripotent stem cell (iPSC)-derived motor neurons from a patient with the p.T994I gene mutation as an model for X-linked dHMN (dHMNX). Patient motor neurons show a marked reduction of ATP7A protein levels in the soma when compared to control motor neurons and failed to upregulate expression of ATP7A under copper-loading conditions. These results recapitulate previous findings obtained in dHMNX patient fibroblasts and in primary cells from a rodent model of dHMNX, indicating that patient iPSC-derived motor neurons will be an important resource for studying the role of copper in the pathogenic processes that lead to axonal degeneration in dHMNX.
编码一种铜转运 P 型 ATP 酶，是导致远端遗传性运动神经病（dHMN）的 23 个基因突变之一，这是一组以运动神经元轴突退行性病变为主的疾病，其病变程度与神经纤维的长度相关。我们从一位 T994I 基因突变的患者中诱导产生多能干细胞（iPSC）衍生的运动神经元，以此作为 X 连锁远端遗传性运动神经病（dHMNX）的模型。与对照组运动神经元相比，患者的运动神经元在胞体中 ATP7A 蛋白水平显著降低，并且在铜负荷条件下无法上调 ATP7A 的表达。这些结果与之前在 dHMNX 患者成纤维细胞和 dHMNX 啮齿动物模型的原代细胞中获得的发现相吻合，表明患者 iPSC 衍生的运动神经元将成为研究铜在导致 dHMNX 轴突退行性病变的致病过程中作用的重要资源。
