A genetic model of amyotrophic lateral sclerosis in zebrafish displays phenotypic hallmarks of motoneuron disease
A genetic model of amyotrophic lateral sclerosis in zebrafish displays phenotypic hallmarks of motoneuron disease
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DOI：
10.1242/dmm.005538
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发表时间：
2010-09-01
影响因子：
4.3
通讯作者：
Beattie, Christine E.
中科院分区：
文献类型：
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作者：
Ramesh, Tennore;Lyon, Alison N.;Beattie, Christine E.
肌萎缩侧索硬化症（ALS）是一种进行性神经退行性疾病，大约80%的患者在诊断后五年内死亡。为了更好地了解ALS，动物模型是必不可少的;然而，只有ALS的啮齿动物模型表现出该疾病的主要特征。在这里，我们报告的代转基因斑马鱼过表达突变体Sod 1。用于产生这些品系的构建体含有斑马鱼sod 1基因和类似于16 kb的侧翼序列。我们产生了表达G93 R突变的细胞系，以及表达野生型Sod 1的细胞系。对两个G93 R株系的研究发现，它们表现出ALS的主要表型。在幼虫和成虫阶段观察到神经肌肉接头的变化。在成年期，G93 R突变体在游泳隧道测试中表现出耐力下降。肌肉分析显示正常的肌肉力量，然而，在最后阶段，鱼表现出运动神经元损失，肌肉萎缩，瘫痪和过早死亡。这些表型在表达更高水平的突变体Sod 1的品系中更严重，并且在过表达野生型Sod 1的品系中不存在。因此，我们已经产生了ALS的脊椎动物模型，以补充现有的哺乳动物模型。
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that, for similar to 80% of patients, is fatal within five years of diagnosis. To better understand ALS, animal models have been essential; however, only rodent models of ALS exhibit the major hallmarks of the disease. Here, we report the generation of transgenic zebrafish overexpressing mutant Sod1. The construct used to generate these lines contained the zebrafish sod1 gene and similar to 16 kb of flanking sequences. We generated lines expressing the G93R mutation, as well as lines expressing wild-type Sod1. Focusing on two G93R lines, we found that they displayed the major phenotypes of ALS. Changes at the neuromuscular junction were observed at larval and adult stages. In adulthood the G93R mutants exhibited decreased endurance in a swim tunnel test. An analysis of muscle revealed normal muscle force, however, at the end stage the fish exhibited motoneuron loss, muscle atrophy, paralysis and premature death. These phenotypes were more severe in lines expressing higher levels of mutant Sod1 and were absent in lines overexpressing wild-type Sod1. Thus, we have generated a vertebrate model of ALS to complement existing mammal models.