NEUROPATHOLOGICAL CHANGES IN 2 LINES OF MICE CARRYING A TRANSGENE FOR MUTANT HUMAN CU,ZN SOD, AND IN MICE OVEREXPRESSING WILD-TYPE HUMAN SOD - A MODEL OF FAMILIAL AMYOTROPHIC-LATERAL-SCLEROSIS (FALS)
NEUROPATHOLOGICAL CHANGES IN 2 LINES OF MICE CARRYING A TRANSGENE FOR MUTANT HUMAN CU,ZN SOD, AND IN MICE OVEREXPRESSING WILD-TYPE HUMAN SOD - A MODEL OF FAMILIAL AMYOTROPHIC-LATERAL-SCLEROSIS (FALS)
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DOI：
10.1016/0006-8993(95)00063-v
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发表时间：
1995-04-03
期刊：
影响因子：
2.9
通讯作者：
GURNEY, ME
中科院分区：
文献类型：
--
作者：
DALCANTO, MC;GURNEY, ME
在家族性肌萎缩性侧索硬化症（FALS）家族中发现的两种不同品系的小鼠G1和G20携带一种突变形式的Cu，Zn SOD的转基因，在其晚期出现了与人类疾病惊人相似的临床和病理变化。我们分析了这些小鼠中枢和周围神经系统病变的分布和特点。受影响最大的结构是脊髓，其次是髓质、脑笔和中脑。疾病的早期特征是前角神经元及其过程的空泡变性，而在晚期，主要变化包括前角神经元的丢失和萎缩，以及这些区域内类似路易体的多个丝状包涵体的沉积。在疾病的晚期，脊髓白质也受累，特别是在前柱和侧柱。后柱也受累，但程度较轻。脑干结构也表现出若干运动核和若干组网状神经元的空泡变性。前根神经和周围神经表现为沃勒氏变性的典型特征。背根神经节，除少数例外，无显著差异。在受影响最严重的小鼠中，后根显示出轻微的变化。将这两种受影响系的变化与过表达野生型小鼠的变化进行比较，而不是突变的人Cu，Zn SOD。这些小鼠从未发生临床疾病，尽管在病理上，它们在脊髓前角和运动轴突发生了非常轻微的空泡改变。本研究表明，尽管SOD的简单过表达可能对运动神经元有害，尽管非常轻微，但突变形式是产生临床疾病和严重病理改变所必需的，在疾病的慢性阶段，与人类家族性ALS有惊人的相似之处。因此，主要的功能增益是由Cu，Zn SOD突变引起的组织损伤的最可能的发病机制。
Two different lines of mice, G1 and G20, carrying a transgene for a mutant form of Cu,Zn SOD, found in a family with familial amyotrophic lateral sclerosis (FALS), develop clinical and pathological changes which are, in their late stages, strikingly similar to those in human disease. We have analyzed the distribution and characteristics of lesions in the central and peripheral nervous systems of such mice. The most affected structure was the spinal cord, followed by the medulla, pens and midbrain. The early stages of the disease were characterized by vacuolar degeneration of anterior horn neurons and their processes, while, in the late stages, the main changes consisted of neuronal loss and atrophy of the anterior horns and the deposition in these areas of multiple filamentous inclusions resembling Lewy bodies. In the late stages of the disease, the white matter of the spinal cord was also involved, particularly in the anterior and lateral columns. Posterior columns were also involved, but to a much lesser degree. The brainstem structures also showed vacuolar degeneration of several motor nuclei and of several groups neurons in the reticular formation. Anterior roots and peripheral nerves showed the classical features of Wallerian degeneration. The dorsal root ganglia, with rare exceptions, were unremarkable. The posterior roots showed mild changes in the most severely affected mice. Changes in these two affected lines were compared to changes in mice overexpressing wild type, rather than mutant human Cu,Zn SOD. These mice never developed clinical disease, although, pathologically, they developed very mild vacuolar changes in the anterior horns of the spinal cord and in motor axons, This study shows that although simple overexpression of SOD may be injurious to motor neurons, albeit very mildly, the mutant form is necessary to produce both clinical disease and severe pathological changes which, in the chronic stage of the disease, have striking similarities to human familial ALS. A dominant gain of function, therefore, is the most likely pathogenesis of tissue injury induced by mutations in Cu,Zn SOD.