Wootz Hanna, Hansson Inga, Korhonen Laura, Näpänkangas Ulla, Lindholm Dan
Department of Neuroscience, Unit of Neurobiology, Uppsala University, Biomedical Centre, Box 587, S-751 23 Uppsala, Sweden.
Biochem Biophys Res Commun. 2004 Sep 10;322(1):281-6. doi: 10.1016/j.bbrc.2004.07.118.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by loss of motoneurons in the spinal cord and brain stem. We have characterized motoneuron death in transgenic mice carrying the mutant human copper/zinc superoxide dismutase, as a model for familial ALS. Previous studies have shown the involvement of mitochondria in nerve cell demise in these animals. We report here an early cleavage of caspase-12, residing in the endoplasmic reticulum (ER), in the spinal cord during the course of the disease. Apart from caspase-12, caspase-9, and caspase-3 were activated in the transgenic ALS mice. Staining with an antibody for nitrotyrosine, as a marker for oxidative stress, showed a large increase in the ALS mice. The results indicate that oxidative and ER induced stress causing caspase-12 activation are involved in neuronal death and disease progression in ALS. Caspase-12 and the ER pathway for cell death may constitute potential novel targets for the treatment of ALS.
肌萎缩侧索硬化症（ALS）是一种神经退行性疾病，其特征是脊髓和脑干中的运动神经元丧失。我们已将携带突变型人类铜/锌超氧化物歧化酶的转基因小鼠中的运动神经元死亡作为家族性ALS的模型进行了表征。先前的研究表明，线粒体参与了这些动物的神经细胞死亡。我们在此报告，在疾病过程中，位于内质网（ER）中的半胱天冬酶-12在脊髓中发生了早期裂解。除了半胱天冬酶-12外，转基因ALS小鼠中的半胱天冬酶-9和半胱天冬酶-3也被激活。用硝基酪氨酸抗体染色作为氧化应激的标志物，结果显示ALS小鼠中有大幅增加。结果表明，氧化应激和内质网诱导的应激导致半胱天冬酶-12激活，参与了ALS中的神经元死亡和疾病进展。半胱天冬酶-12和细胞死亡的内质网途径可能构成治疗ALS的潜在新靶点。
