Mouse motor neuron disease caused by truncated SOD1 with or without C-terminal modification
Mouse motor neuron disease caused by truncated SOD1 with or without C-terminal modification
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DOI：
10.1016/j.molbrainres.2004.11.019
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发表时间：
2005-04-27
期刊：
影响因子：
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通讯作者：
Nakashima, K
中科院分区：
文献类型：
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作者：
Watanabe, Y;Yasui, K;Nakashima, K
Cu/Zn超氧化物歧化酶（SOD I）基因突变与部分家族性肌萎缩侧索硬化症（FALS）有关。我们先前报道了一个FALS家族，其成员具有突变形式的SOD 1，其特征在于在SOD 1基因的密码子126处缺失2个碱基对（bp）。为了研究这种突变的细胞后果，我们生产了表达正常和突变的人类SOD 1拷贝的转基因小鼠：野生型SOD 1（W），在C-末端具有FLAG表位的野生型SOD 1（WF），具有2-bp缺失的突变SOD 1（D），SOD 1基因2-bp缺失，FLAG（DF），（D和DF）表现出明显的ALS样运动症状，而与正常SOD 1杂合子的小鼠（W和WF）则没有。D系和DF系纯合子出现ALS症状的年龄早于杂合子，死亡早于杂合子。通过北方印迹分析，在这些细胞系中证实了所有人SOD 1的mRNA。所有的人SOD 1蛋白，除了D突变体，可通过免疫印迹检测。D蛋白仅在通过免疫沉淀浓缩时才得到确认。神经病理学上，脊髓运动神经元丢失和反应性胶质增生是症状线的共同特征。这些小鼠的运动神经元也有嗜酸性包涵体，其生化和病理特征与具有相同突变的人类FALS患者非常相似。这一有趣的模型将提供一个重要的信息来源的发病机制的FALS。(c)2005 Elsevier B. V.保留所有权利。
Mutation of Cu/Zn superoxide dismutase (SOD I) contributes to a portion of the cases of familial amyotrophic lateral sclerosis (FALS). We previously reported on a FALS family whose members had a mutant form of SOD1 characterized by a 2-base pair (bp) deletion at codon 126 of the SOD1 gene. To investigate the cellular consequences of this mutation, we produced transgenic mice that expressed normal and mutated copies of human SOD 1: wild-type SOD1 (W), wild-type SOD1 with a FLAG epitope at C-terminal (WF), mutated SOD1 with the 2-bp deletion (D), and SOD1 with the 2-bp deletion with FLAG (DF).The mice heterozygotic for the human mutated SOD1 (D and DF) showed distinct ALS-like motor symptoms, whereas the mice heterozygotic for the normal SOD 1 (W and WF) mice did not. Homozygotes of D and DF lines showed the ALS symptoms at an earlier age and died earlier than the heterozygotes. By Northern blot analysis, the mRNAs for all human SOD1s were confirmed in these lines. All the human SOD1 proteins, except the D mutant, were detectable by immunoblot. The D protein was only confirmed when it was concentrated by immunoprecipitation. Neuropathologically, loss of spinal motor neurons and reactive gliosis were common features in the symptomatic lines. The remaining motor neurons in these mice also exhibited eosinophilic inclusions.The biochemical and pathological characteristics of these mice are quite similar to those of human FALS patients with same mutation. This intriguing model will provide an important source of information of the pathogenesis of FALS. (c) 2005 Elsevier B.V. All rights reserved.