Oxidative stress, mutant SOD1, and neurofilament pathology in transgenic mouse models of human motor neuron disease.
Oxidative stress, mutant SOD1, and neurofilament pathology in transgenic mouse models of human motor neuron disease.
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发表时间：
1997-04
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通讯作者：
Pang-Hsien Tu;M. Gurney;Jean-Pierre Julien;V. Lee;J. Trojanowski
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作者：
Pang-Hsien Tu;M. Gurney;Jean-Pierre Julien;V. Lee;J. Trojanowski
肌萎缩侧索硬化症（ALS）是一种神经退行性疾病，主要影响脊髓和脑干的运动神经元。所有 ALS 病例中约 10% 为家族性 (FALS)，以常染色体显性遗传方式遗传。五分之一的 FALS 患者携带铜/锌超氧化物歧化酶 (SOD1) 基因突变，并且已经设计了多个转基因小鼠品系来表达与 FALS 相关的 SOD1 基因突变形式。值得注意的是，许多转基因小鼠品系都出现了类似于人类 FALS 的运动神经元疾病 (MND)。人类 SOD1 突变诱导的氧化应激被认为在 FALS 和突变 SOD1 转基因小鼠中观察到的 FALS 样 MND 的发病机制中发挥重要作用。例如，这些小鼠的两个品系显示出脊髓神经元中线粒体和内质网的显着变性。此外，最近的研究表明富含神经丝（NF）的球体。这些突变型 SOD1 转基因小鼠的脊髓运动神经元中出现路易体样 NF 包涵体、泛素免疫反应性改变和高尔基体断裂。由于这些病变再现了人类 ALS 的标志性异常，因此突变型 SOD1 转基因小鼠为旨在阐明 ALS 发病机制的研究提供了有用的模型。此外，过度表达 NF 蛋白的转基因小鼠也会产生与人类 MND 相似的临床和病理表型，并且 NF 基因的多态性已与 ALS 患者相关。总的来说，这些观察结果表明 NF 蛋白异常与这种疾病的发病机制有关。因此，这篇综述总结了对 ALS 运动神经元变性机制的最新见解，这些机制是从对这种神经退行性疾病的新动物模型的研究中得出的。
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects motor neurons in the spinal cord and brain stem. About 10% of all ALS cases are familial (FALS), inherited in an autosomal dominant manner. One fifth of FALS patients carry mutations in the Cu/Zn superoxide dismutase (SOD1) gene, and several lines of transgenic mice have been engineered to express mutant forms of the SOD1 gene that are linked to FALS. Significantly, many of these transgenic lines of mice develop a motor neuron disease (MND) that resembles human FALS. Oxidative stress induced by human SOD1 mutations is believed to play an important role in the pathogenesis of FALS and the FALS-like MND seen in the mutant SOD1 transgenic mice. For example, two lines of these mice showed prominent degeneration of mitochondria and endoplasmic reticulum in spinal cord neurons. Furthermore, recent studies have shown that neurofilament (NF)-rich spheroids. Lewy body-like NF inclusions, altered ubiquitin immunoreactivity, and Golgi fragmentation occur in the spinal cord motoneurons of these mutant SOD1 transgenic mice. Because these lesions recapitulate hallmark abnormalities of human ALS, mutant SOD1 transgenic mice provide a useful model for studies designed to elucidate the pathogenesis of ALS. Furthermore, transgenic mice that overexpress NF proteins also develop a clinical and pathologic phenotype similar to human MND, and polymorphisms in an NF gene have been linked to patients with ALS. Collectively, these observations implicate NF protein abnormalities in the pathogenesis of this disorder. Accordingly, this review summarizes recent insights into mechanisms of motor neuron degeneration in ALS that have emerged from studies of these new animal models of this neurodegenerative disease.