Stieber A, Gonatas J O, Gonatas N K
Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, 609a Stellar-Chance, 422 Curie Blvd. /6100, Philadelphia, PA 19104, USA.
J Neurol Sci. 2000 Aug 15;177(2):114-23. doi: 10.1016/s0022-510x(00)00351-8.
Mice expressing the G93A and other mutations of Cu,Zn superoxide dismutase (SOD1(G93A)) are valid models for the familial form of amyotrophic lateral sclerosis (FALS) with SOD1 mutations and, probably, for sporadic ALS. Adult mice become progressively paralyzed and show most of the histopathological lesions reported in sporadic ALS, i.e. neuronal loss, astrogliosis, ubiquitin and Lewy body-like inclusions, dystrophic axons and fragmentation of the Golgi apparatus (GA) of motor neurons. In transgenic mice, the mutant protein and ubiquitin aggregate within pathological 13 nm thick filaments [Stieber A, Gonatas JO, Gonatas NK. J Neurol Sci 2000;173:53-62]. This immunocytochemical and quantitative study of mice expressing SOD1(G93A) establishes the chronological order and cellular localization of aggregates of SOD1 and their correlation with fragmentation of the GA. Young asymptomatic mice expressing SOD1(G93A) showed aggregates of mutant SOD1 within neurites, prior to the detection of SOD1 in the perikarya of spinal cord motor neurons and astrocytes. Both dendrites and the periaxonal oligodendroglial cytoplasm, surrounding atrophic axons, contained SOD1 as revealed by immunoelectron microscopy The perikarya of a small percentage of spinal cord motor neurons contained both fragmented GA and aggregates of SOD1; however, about 50% of motor neurons with fragmented GA did not contain SOD1 in the perikaryon, suggesting that aggregates of mutant protein may not directly cause fragmentation of the GA. The mechanism of the putative toxic effect by the mutant protein remains to be clarified. The isolation and biochemical characterization of the filamentous aggregates of mutant protein and ubiquitin from spinal cords of transgenic mice expressing mutations of the SOD1 gene may offer clues on pathogenetic mechanisms.
表达G93A及其他铜锌超氧化物歧化酶突变（SOD1(G93A)）的小鼠是伴有SOD1突变的家族性肌萎缩侧索硬化症（FALS）以及可能的散发性肌萎缩侧索硬化症的有效模型。成年小鼠会逐渐瘫痪，并出现散发性肌萎缩侧索硬化症中报道的大多数组织病理学病变，即神经元丢失、星形胶质细胞增生、泛素和路易体样包涵体、营养不良性轴突以及运动神经元高尔基体（GA）的碎片化。在转基因小鼠中，突变蛋白和泛素聚集在病理性的13纳米厚的细丝中[Stieber A, Gonatas JO, Gonatas NK. 《神经科学杂志》2000年；173:53 - 62]。这项对表达SOD1(G93A)的小鼠进行的免疫细胞化学和定量研究确定了SOD1聚集物的时间顺序和细胞定位，以及它们与GA碎片化的相关性。表达SOD1(G93A)的年轻无症状小鼠在脊髓运动神经元和星形胶质细胞的胞体中检测到SOD1之前，其神经突内就出现了突变型SOD1的聚集物。免疫电子显微镜显示，萎缩轴突周围的树突和轴突周围少突胶质细胞质中都含有SOD1。一小部分脊髓运动神经元的胞体同时含有碎片化的GA和SOD1聚集物；然而，约50%有GA碎片化的运动神经元胞体中不含SOD1，这表明突变蛋白的聚集物可能不会直接导致GA的碎片化。突变蛋白假定的毒性作用机制仍有待阐明。从表达SOD1基因突变的转基因小鼠脊髓中分离并对突变蛋白和泛素的丝状聚集物进行生化特性分析，可能会为发病机制提供线索。
