Zhang Lin, Haraguchi Seiki, Koda Tadayuki, Hashimoto Kenji, Nakagawara Akira
Division of Biochemistry and Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-Ku, Chiba 260-8717, Japan.
J Biomed Biotechnol. 2011;2011:831092. doi: 10.1155/2011/831092. Epub 2010 Oct 3.
Amyotrophic lateral sclerosis (ALS) is the most frequent adult-onset motor neuron disease. Approximately 20% cases of familial ALS show the mutation in the superoxide dismutase-1 (SOD1) gene. We previously demonstrated that homologue to E6AP carboxyl terminus- (HECT-) type ubiquitin protein E3 ligase (NEDL1) physically bind to mutated SOD1 protein but not wild-type SOD1 and promote the degradation of mutated SOD1 protein through ubiquitin-mediated proteasome pathway. To further understand the role of NEDL1 involved in the pathogenesis of familial ALS, we generated transgenic mice with human NEDL1 cDNA. The transgenic mice with human NEDL1 expression showed motor dysfunctions in rotarod, hanging wire, and footprint pattern examination. Histological studies indicated degeneration of neurons in the lumbar spinal cord and muscle atrophy. The number of activated microglia in the spinal cord of transgenic mice was significantly higher than that of wild-type mice, suggesting that inflammation might be observed in the spinal cord of transgenic mice. In conclusion, these findings suggest that the human NEDL1 transgenic mice might develop ALS-like symptoms, showing signs of motor abnormalities, accompanied with significant reduction in muscle strength.
肌萎缩侧索硬化症（ALS）是最常见的成人起病的运动神经元疾病。约20%的家族性ALS病例显示超氧化物歧化酶-1（SOD1）基因突变。我们之前证明，E6AP羧基末端同源物（HECT）型泛素蛋白E3连接酶（NEDL1）与突变的SOD1蛋白发生物理结合，但不与野生型SOD1结合，并通过泛素介导的蛋白酶体途径促进突变SOD1蛋白的降解。为了进一步了解NEDL1在家族性ALS发病机制中的作用，我们构建了携带人NEDL1 cDNA的转基因小鼠。表达人NEDL1的转基因小鼠在转棒试验、悬线试验和足迹模式检查中表现出运动功能障碍。组织学研究表明，腰椎脊髓中的神经元发生退化，肌肉出现萎缩。转基因小鼠脊髓中活化小胶质细胞的数量显著高于野生型小鼠，这表明在转基因小鼠的脊髓中可能观察到炎症。总之，这些发现表明，人NEDL1转基因小鼠可能会出现类似ALS的症状，表现出运动异常的迹象，同时伴有肌肉力量的显著下降。
