Overexpressed wild-type superoxide dismutase 1 exhibits amyotrophic lateral sclerosis-related misfolded conformation in induced pluripotent stem cell-derived spinal motor neurons
Overexpressed wild-type superoxide dismutase 1 exhibits amyotrophic lateral sclerosis-related misfolded conformation in induced pluripotent stem cell-derived spinal motor neurons
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DOI：
10.1097/wnr.0000000000000922
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发表时间：
2018-01-03
期刊：
影响因子：
1.7
通讯作者：
Inoue, Haruhisa
中科院分区：
文献类型：
--
作者：
Komatsu, Kenichi;Imamura, Keiko;Inoue, Haruhisa
肌萎缩侧索硬化症（ALS）是一种迟发性、致命性疾病，其中运动神经元选择性退化。超氧化物歧化酶1（SOD 1）是家族性ALS的致病基因，突变型SOD 1转基因小鼠重现了ALS的表型。对这些小鼠的分析表明，运动神经元中错误折叠的SOD 1蛋白质积累。在具有SOD1突变的家族性ALS患者和散发性ALS患者的脊髓运动神经元中发现了错误折叠的SOD1积累。然而，目前还不清楚是什么条件导致野生型SOD1错误折叠的患者没有SOD1突变。在这里，我们从突变型SOD1转基因小鼠，野生型SOD1转基因小鼠和对照小鼠中产生诱导多能干细胞，并将其分化为脊髓运动神经元以分析错误折叠的SOD1积累。我们发现，错误折叠的SOD1蛋白积累在突变型和野生型SOD1转基因小鼠的脊髓运动神经元的特异性抗体对SOD1的错误折叠构象检测。这些结果表明，野生型SOD1的表达水平的增加可能会加速ALS的病理，我们的体外模型将是一个有用的工具，错误折叠SOD1的研究。
Amyotrophic lateral sclerosis (ALS) is a late-onset, fatal disorder in which motor neurons selectively degenerate. Superoxide dismutase 1 (SOD1) was found to be a causative gene of familial ALS, and mutant SOD1 transgenic mice recapitulated ALS phenotypes. Analysis of these mice showed accumulation of misfolded SOD1 protein in motor neurons. Misfolded SOD1 accumulation was found in spinal motor neurons of both familial ALS patients with the SOD1 mutation and sporadic ALS patients. However, it is unclear what condition causes wild-type SOD1 misfolding in patients without the SOD1 mutation. Here, we generated induced pluripotent stem cells from mutant SOD1 transgenic mice, wild-type SOD1 transgenic mice, and control mice, and differentiated them into spinal motor neurons to analyze misfolded SOD1 accumulation. We found that misfolded SOD1 protein was accumulated in spinal motor neurons of both mutant and wild-type SOD1 transgenic mice as detected by a specific antibody against the misfolded conformation of SOD1. These results suggest that an increased expression level of wild-type SOD1 may accelerate the ALS pathology and that our in vitro model would be a useful tool for misfolded SOD1 research.