Ghadge G D, Lee J P, Bindokas V P, Jordan J, Ma L, Miller R J, Roos R P
Department of Neurology, The University of Chicago, Chicago, Illinois 60637, USA.
J Neurosci. 1997 Nov 15;17(22):8756-66. doi: 10.1523/JNEUROSCI.17-22-08756.1997.
Mutations in human Cu/Zn superoxide dismutase-1 (SOD) cause approximately 20% of cases of familial amyotrophic lateral sclerosis (FALS). We investigated the mechanism of mutant SOD-induced neuronal degeneration by expressing wild-type and mutant SODs in neuronal cells by means of infection with replication-deficient recombinant adenoviruses. Expression of two FALS-related mutant SODs (A4V and V148G) caused death of differentiated PC12 cells, superior cervical ganglion neurons, and hippocampal pyramidal neurons. Cell death included many features typical of apoptosis. Death could be prevented by copper (Cu2+) chelators, Bcl-2, glutathione, vitamin E, and inhibitors of caspases. Mutant SOD-expressing PC12 cells had higher rates of superoxide (O2-) production under a variety of conditions. The results support the hypothesis that mutant SOD induced-neurodegeneration is associated with disturbances of neuronal free radical homeostasis.
人类铜锌超氧化物歧化酶-1（SOD）突变导致约20%的家族性肌萎缩侧索硬化症（FALS）病例。我们通过用复制缺陷型重组腺病毒感染神经元细胞来表达野生型和突变型SOD，从而研究突变型SOD诱导神经元变性的机制。两种与FALS相关的突变型SOD（A4V和V148G）的表达导致分化的PC12细胞、颈上神经节神经元和海马锥体神经元死亡。细胞死亡包括许多典型的凋亡特征。铜（Cu2+）螯合剂、Bcl-2、谷胱甘肽、维生素E和半胱天冬酶抑制剂可预防细胞死亡。在各种条件下，表达突变型SOD的PC12细胞具有更高的超氧化物（O2-）产生率。这些结果支持了这样的假设，即突变型SOD诱导的神经变性与神经元自由基稳态的紊乱有关。
