Gong Y H, Parsadanian A S, Andreeva A, Snider W D, Elliott J L
Department of Neurology, University of Texas, Southwestern Medical Center, Dallas, Texas 75235, USA.
J Neurosci. 2000 Jan 15;20(2):660-5. doi: 10.1523/JNEUROSCI.20-02-00660.2000.
Evidence garnered from both human autopsy studies and genetic animal models has suggested a potential role for astrocytes in the pathogenesis of amyotrophic lateral sclerosis (ALS). Currently, mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) represent the only known cause of motoneuron loss in the disease, producing 21q linked familial ALS (FALS). To determine whether astrocytic dysfunction has a primary role in familial ALS, we have generated multiple lines of transgenic mice expressing G86R mutant SOD1 restricted to astrocytes. In GFAP-m SOD1 mice, astrocytes exhibit significant hypertrophy and increased GFAP reactivity as the animals mature. However, GFAP-mutant SOD1 transgenic mice develop normally and do not experience spontaneous motor deficits with increasing age. Histological examination of spinal cord in aged GFAP-mSOD1 mice reveals normal motoneuron and microglial morphology. These results indicate that 21q linked FALS is not a primary disorder of astrocytes, and that expression of mutant SOD1 restricted to astrocytes is not sufficient to cause motoneuron degeneration in vivo. Expression of mutant SOD1 in other cell types, most likely neurons, is critical for the initiation of disease.
来自人体尸检研究和基因动物模型的证据表明，星形胶质细胞在肌萎缩侧索硬化症（ALS）的发病机制中可能发挥作用。目前，编码铜/锌超氧化物歧化酶（SOD1）的基因突变是该疾病中已知的唯一导致运动神经元丧失的原因，可引发21号染色体连锁的家族性ALS（FALS）。为了确定星形胶质细胞功能障碍在家族性ALS中是否起主要作用，我们构建了多条转基因小鼠品系，这些小鼠只在星形胶质细胞中表达G86R突变型SOD1。在GFAP-m SOD1小鼠中，随着动物成熟，星形胶质细胞表现出明显的肥大和GFAP反应性增加。然而，GFAP-突变型SOD1转基因小鼠发育正常，且不会随着年龄增长出现自发的运动缺陷。对老年GFAP-mSOD1小鼠脊髓的组织学检查显示运动神经元和小胶质细胞形态正常。这些结果表明，21号染色体连锁的FALS不是星形胶质细胞的原发性疾病，并且仅在星形胶质细胞中表达突变型SOD1不足以在体内引起运动神经元变性。突变型SOD1在其他细胞类型（很可能是神经元）中的表达对于疾病的起始至关重要。
