Transgenic animal models of familial amyotrophic lateral sclerosis
Transgenic animal models of familial amyotrophic lateral sclerosis
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DOI：
10.1007/bf03160575
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发表时间：
1997-05-01
影响因子：
6
通讯作者：
Gurney, ME
中科院分区：
文献类型：
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作者：
Gurney, ME
肌萎缩性侧索硬化症（ALS）有散发性和家族性两种形式，它们具有非常相似的临床表现和病程。大约20%的ALS家族性病例是由编码Cu，Zn超氧化物歧化酶（SOD）的SOD 1基因突变引起的。在患者中发现了超过30种不同的SOD1基因突变。大多数是错义突变，导致一种氨基酸被另一种氨基酸取代。在家族性ALS中未能发现缺失表明突变蛋白是发病所需的。转基因小鼠的研究表明，家族性ALS是由SOD1基因的功能获得性突变引起的。当在转基因小鼠中高水平表达时，突变的人Cu，Zn SOD引起类似于人ALS的临床疾病。脊髓和脑干中运动神经元的选择性变性伴有进行性运动损伤。家族性ALS转基因模型的发病机制是一个连续的两步过程，其中自由基介导的损伤累积到阈值，通过谷氨酸介导的兴奋性毒性机制触发灾难性运动神经元损失。支持这一假设的证据来自抗氧化剂和多巴胺能神经传递抑制剂的治疗研究。
Amyotrophic lateral sclerosis (ALS) occurs in both sporadic and familial forms, which have very similar clinical presentation and course. Approximately 20% of the familial cases of ALS are caused by mutation of the SOD1 gene encoding Cu,Zn superoxide dismutase (SOD). Over 30 different SOD1 gene mutations have been found in patients. Most are missense mutations that cause the substitution of one amino acid for another. The failure to find deletions in familial ALS suggests that the mutant protein is required for pathogenesis. Studies in transgenic mice indicate that familial ALS is caused by gain-of-function mutations in the SOD1 gene. These enhance formation of free radicals by the mutant enzyme, When expressed at high levels in transgenic mice, mutant human Cu,Zn SOD causes a clinical disease that resembles human ALS. Selective degeneration of motor neurones in the spinal cord and brainstem is accompanied by progressive motor impairment. Pathogenesis in the transgenic model of familial ALS is a sequential, two-step process in which damage mediated by free radicals accumulates to a threshold that triggers catastrophic motor neurone loss through glutamate-mediated, excitotoxic mechanisms. Evidence in support of this hypothesis comes from therapeutic studies with antioxidants and inhibitors of glutamatergic neurotransmission.