Restricted expression of G86R Cu/Zn superoxide dismutase in astrocytes results in astrocytosis but does not cause motoneuron degeneration
Restricted expression of G86R Cu/Zn superoxide dismutase in astrocytes results in astrocytosis but does not cause motoneuron degeneration
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DOI：
10.1523/jneurosci.20-02-00660.2000
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发表时间：
2000-01-15
影响因子：
5.3
通讯作者：
Elliott, JL
中科院分区：
文献类型：
--
作者：
Gong, YH;Parsadanian, AS;Elliott, JL
从人类尸检研究和遗传动物模型中获得的证据表明星形胶质细胞在肌萎缩侧索硬化症（ALS）的发病机制中具有潜在作用。目前，编码Cu/Zn超氧化物歧化酶（SOD 1）的基因突变是该疾病中运动神经元丢失的唯一已知原因，产生21 q连锁家族性ALS（FALS）。为了确定星形胶质细胞功能障碍是否在家族性ALS中具有主要作用，我们已经产生了多个转基因小鼠系，其表达限于星形胶质细胞的G86 R突变体SOD 1。在GFAP-m SOD 1小鼠中，随着动物成熟，星形胶质细胞表现出显著的肥大和增加的GFAP反应性。然而，GFAP突变的SOD 1转基因小鼠发育正常，随着年龄的增长不会出现自发性运动缺陷。老年GFAP-mSOD 1小鼠脊髓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 q连锁的FALS不是星形胶质细胞的原发性疾病，并且仅限于星形胶质细胞的突变体SOD 1的表达不足以引起体内运动神经元变性。突变型SOD 1在其他细胞类型（最有可能是神经元）中的表达对于疾病的发生至关重要。
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.