Molecular mechanism and gene therapy of familial ALS

肌萎缩性侧索硬化症（ALS）是一种主要影响中枢神经系统运动神经元的退行性疾病。目前尚无有效的治疗方法，病程通常为2-5年。大约5-10%的ALS被认为是家族性（FALS），常染色体显性遗传，或较少的隐性遗传。我们报告了七个FALS家族与四种不同的铜/锌SOD基因错义突变（D6F、H46R、L84V、A90V、I104F、S134N和V148I）相关，每个家族都有独特的临床特征。肌萎缩侧索硬化症患者的脊髓运动神经元中存在酪氨酸蛋白的硝化作用，而对照组中没有。以G93A Cu/Zn SOD基因突变转基因小鼠为实验材料，观察到坐骨神经结扎对快速轴突运输的早期选择性损伤。此外，脊髓运动神经元中Akt、PI3K等细胞存活信号的免疫反应性早期下降，而caspases、TUNEL等细胞死亡信号的免疫反应性直到运动神经元死亡前期才出现阳性，说明濒死运动神经元中细胞存活与死亡信号的严重失衡。此外，-介导的Lace基因在转基因症状小鼠的肌肉和脊髓运动神经元中有效转移表达，为人类ALS患者的治疗奠定了基础。

Amyotrophic lateral sclerosis (ALS) is a degenerative disorder affecting predominantly motor neurons in the central nervous system. There has been no effective treatment, and the duration is usually 2-5 years. About 5-10% of ALS is thought to be familial (FALS) with an autosomal dominant inheritance, or less often recessive.We report here seven FALS families associated with four different missense mutations of the Cu/Zn SOD gene (D6F, H46R, L84V, A90V, I104F, S134N, and V148I), and each family has unique clinical characteristics. Protein tyrosin nitration of spinal motor neurons was found in ALS patients, but not in control subjects. With transgenic mice of G93A Cu/Zn SOD gene mutation, we found early and selective impairment of fast axonal transport by ligation of sciatic nerves. Furthermore, immunoreactivity of cell survival signal such as Akt and PI3K showed early decrease in spinal motor neurons, but immunoreactivities for cell death signals such as caspases or TUNEL was not positive until the advance stage of motor neuron death, indicating a critical imbalance of cell survival and death signals in dying motor neurons. In addition, -mediated Lace gene was effectively transferred and expressed in muscles and spinal motor neurons in transgenic symptomatic mice, and established a therapic basis for human ALS patients.