Tu P H, Raju P, Robinson K A, Gurney M E, Trojanowski J Q, Lee V M
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, 19104-4283, USA.
Proc Natl Acad Sci U S A. 1996 Apr 2;93(7):3155-60. doi: 10.1073/pnas.93.7.3155.
Mutations in the human Cu,Zn superoxide dismutase gene (SOD1) are found in 20% of kindreds with familial amyotrophic lateral sclerosis. Transgenic mice (line G1H) expressing a human SOD1 containing a mutation of Gly-93 --> Ala (G93A) develop a motor neuron disease similar to familial amyotrophic lateral sclerosis, but transgenic mice (line N1029) expressing a wild-type human SOD1 transgene do not. Because neurofilament (NF)-rich inclusions in spinal motor neurons are characteristic of amyotrophic lateral sclerosis, we asked whether mutant G1H and/or N1029 mice develop similar NF lesions. NF inclusions (i.e., spheroids, Lewy body-like inclusions) were first detected in spinal cord motor neurons of the G1H mice at 82 days of age about the time these mice first showed clinical evidence of disease. Other neuronal intermediate filament proteins (alpha-internexin, peripherin) also accumulated in these spheroids. The onset of accumulations of ubiquitin immunoreactivity in the G1H mice paralleled the emergence of vacuoles and NF-rich spheroids in neurons, but they did not colocalize exclusively with spheroids. In contrast, NF inclusions were not seen in the N1029 mice until they were 132 days old, and ubiquitin immunoreactivity was not increased in the N1029 mice even at 199 days of age. Astrocytosis in spinal cord was associated with a marked increase in glial fibrillary acidic protein immunoreactivity in the G1H mice, but not in the N1029 mice. Finally, comparative studies revealed a striking similarity between the cytoskeletal pathology in the G1H transgenic mice and in patients with amyotrophic lateral sclerosis. These findings link a specific SOD1 mutation with alterations in the neuronal cytoskeleton of patients with amyotrophic lateral sclerosis. Thus, neuronal cytoskeletal abnormalities may be implicated in the pathogenesis of human familial amyotrophic lateral sclerosis.
在20%的家族性肌萎缩侧索硬化症家系中发现了人类铜锌超氧化物歧化酶基因（SOD1）的突变。表达含有甘氨酸93突变为丙氨酸（G93A）的人类SOD1的转基因小鼠（G1H系）会患上一种与家族性肌萎缩侧索硬化症相似的运动神经元疾病，但表达野生型人类SOD1转基因的转基因小鼠（N1029系）则不会。由于脊髓运动神经元中富含神经丝（NF）的包涵体是肌萎缩侧索硬化症的特征，我们询问突变的G1H和/或N1029小鼠是否会出现类似的NF病变。NF包涵体（即球形小体、路易体样包涵体）最早在82日龄的G1H小鼠脊髓运动神经元中被检测到，此时这些小鼠首次出现疾病的临床证据。其他神经元中间丝蛋白（α-中间丝蛋白、外周蛋白）也在这些球形小体中积累。G1H小鼠中泛素免疫反应性积累的开始与神经元中液泡和富含NF的球形小体的出现平行，但它们并非仅与球形小体共定位。相比之下，N1029小鼠直到132日龄才出现NF包涵体，甚至在199日龄时，N1029小鼠中的泛素免疫反应性也没有增加。脊髓中的星形细胞增生与G1H小鼠中胶质纤维酸性蛋白免疫反应性的显著增加有关，但在N1029小鼠中则没有。最后，比较研究揭示了G1H转基因小鼠和肌萎缩侧索硬化症患者的细胞骨架病理学之间存在惊人的相似性。这些发现将特定的SOD1突变与肌萎缩侧索硬化症患者神经元细胞骨架的改变联系起来。因此，神经元细胞骨架异常可能与人类家族性肌萎缩侧索硬化症的发病机制有关。
