Yoshihara Tsuyoshi, Ishigaki Shinsuke, Yamamoto Masahiko, Liang Yideng, Niwa Jun-ichi, Takeuchi Hideyuki, Doyu Manabu, Sobue Gen
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
J Neurochem. 2002 Jan;80(1):158-67. doi: 10.1046/j.0022-3042.2001.00683.x.
Familial amyotrophic lateral sclerosis (FALS)-linked mutations in copper-zinc superoxide dismutase (SOD1) cause motor neuron death through one or more acquired toxic properties. We analyzed the molecular mechanism underlying motor neuron degeneration in the transgenic mouse model expressing the SOD1 gene with G93A mutation. Using cDNA microarray, the differentially expressed genes were identified in the spinal cords of G93A mice, 30 being elevated and seven decreased. cDNA microarray analysis to monitor gene expression during neurodegeneration revealed an up-regulation of genes related to an inflammatory process, such as the tumor necrosis factor-alpha (TNF-alpha) gene, resulting from glial cell activation, together with the change in apoptosis-related gene expression, such as caspase-1. The increased expression of the inflammation- and apoptosis-related genes occurred at 11 weeks of age in the presymptomatic stage prior to motor neuron death. These results suggest a mechanism of neurodegeneration that includes an inflammatory response as an important component. Thus, ALS has paralleled other neurodegenerative disorders, such as Alzheimer's and prion diseases, in which the inflammatory process is believed to participate directly in neuronal death.
与家族性肌萎缩侧索硬化症（FALS）相关的铜锌超氧化物歧化酶（SOD1）突变通过一种或多种获得性毒性特性导致运动神经元死亡。我们分析了表达G93A突变的SOD1基因的转基因小鼠模型中运动神经元变性的分子机制。使用cDNA微阵列，在G93A小鼠的脊髓中鉴定出差异表达的基因，其中30个基因表达上调，7个基因表达下调。通过cDNA微阵列分析监测神经变性过程中的基因表达，结果显示，由于胶质细胞激活，与炎症过程相关的基因（如肿瘤坏死因子-α（TNF-α）基因）上调，同时凋亡相关基因（如半胱天冬酶-1）的表达也发生了变化。炎症和凋亡相关基因的表达增加发生在运动神经元死亡前的症状前期，即11周龄时。这些结果提示了一种神经变性机制，其中炎症反应是一个重要组成部分。因此，肌萎缩侧索硬化症与其他神经退行性疾病（如阿尔茨海默病和朊病毒病）类似，在这些疾病中，炎症过程被认为直接参与神经元死亡。
