Dal Canto M C, Gurney M E
Department of Pathology (Neuropathology), Northwestern University Medical School, Chicago, IL 60611, USA.
Brain Res. 1995 Apr 3;676(1):25-40. doi: 10.1016/0006-8993(95)00063-v.
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, pons and midbrain. The early stages of the disease were characterized by vascular 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.
在一个患有家族性肌萎缩侧索硬化症（FALS）的家族中发现了两种携带突变型铜锌超氧化物歧化酶（Cu,Zn SOD）转基因的不同品系小鼠，即G1和G20，它们会出现临床和病理变化，在疾病晚期与人类疾病的变化极为相似。我们分析了此类小鼠中枢和外周神经系统中病变的分布及特征。受影响最严重的结构是脊髓，其次是延髓、脑桥和中脑。疾病早期的特征是前角神经元及其突起的血管变性，而在疾病晚期，主要变化包括神经元丢失、前角萎缩以及这些区域出现类似于路易小体的多个丝状包涵体沉积。在疾病晚期，脊髓白质也受到累及，尤其是在前索和侧索。后索也有累及，但程度要轻得多。脑干结构还显示出几个运动核团和网状结构中几组神经元的空泡变性。前根和外周神经呈现出华勒变性的典型特征。背根神经节除极少数情况外并无明显异常。在受影响最严重的小鼠中，后根出现了轻微变化。将这两个受影响品系的变化与过表达野生型而非突变型人类Cu,Zn SOD的小鼠的变化进行了比较。这些小鼠从未出现临床疾病，尽管在病理上它们在脊髓前角和运动轴突中出现了非常轻微的空泡变化。这项研究表明，虽然超氧化物歧化酶的简单过表达可能对运动神经元有损害，尽管非常轻微，但突变形式对于产生临床疾病和严重病理变化是必要的，在疾病的慢性阶段，这些变化与人类家族性肌萎缩侧索硬化症有惊人的相似之处。因此，功能的显性获得最有可能是由铜锌超氧化物歧化酶突变引起组织损伤的发病机制。
