Andreassen O A, Ferrante R J, Klivenyi P, Klein A M, Shinobu L A, Epstein C J, Beal M F
Neurochemistry Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, USA.
Ann Neurol. 2000 Apr;47(4):447-55.
The pathogenesis of neuronal cell death as a consequence of mutations in copper/zinc superoxide dismutase (SOD1) associated with familial amyotrophic lateral sclerosis may involve oxidative damage and mitochondrial dysfunction. We examined whether crossing transgenic mice with the G93A SOD1 mutation with transgenic mice with a partial depletion of manganese superoxide dismutase (SOD2) would affect the disease phenotype. Compared with G93A mice alone, the mice with partial deficiency of SOD2 and the G93A SOD1 mutation showed a significant decrease in survival and an exacerbation of motor deficits detected by rotorod testing. There was a significant exacerbation of loss of motor neurons and substantia nigra dopaminergic neurons in the G93A mice with a partial deficiency of SOD2 compared with G93A mice at 110 days. Microvesiculation of large motor neurons was more prominent in the G93A mice with a partial deficiency of SOD2 compared with G93A mice at 90 days. These findings provide further evidence that both oxidative damage and mitochondrial dysfunction may play a role in the pathogenesis of motor neuron death associated with mutations in SOD1.
与家族性肌萎缩侧索硬化相关的铜/锌超氧化物歧化酶（SOD1）突变导致神经元细胞死亡的发病机制可能涉及氧化损伤和线粒体功能障碍。我们研究了将携带G93A SOD1突变的转基因小鼠与锰超氧化物歧化酶（SOD2）部分缺失的转基因小鼠杂交是否会影响疾病表型。与单独的G93A小鼠相比，SOD2部分缺乏且携带G93A SOD1突变的小鼠存活率显著降低，转棒试验检测到的运动功能缺陷加剧。与110天时的G93A小鼠相比，SOD2部分缺乏的G93A小鼠运动神经元和黑质多巴胺能神经元的损失显著加剧。与90天时的G93A小鼠相比，SOD2部分缺乏的G93A小鼠中大运动神经元的微囊泡化更为明显。这些发现进一步证明，氧化损伤和线粒体功能障碍可能在与SOD1突变相关的运动神经元死亡发病机制中起作用。
