SOD1 targeted to the mitochondrial intermembrane space prevents motor neuropathy in the Sod1 knockout mouse
SOD1 targeted to the mitochondrial intermembrane space prevents motor neuropathy in the Sod1 knockout mouse
复制标题
DOI：
10.1093/brain/awq314
复制
发表时间：
2011-01-01
期刊：
影响因子：
14.5
通讯作者：
Glass, Jonathan D.
中科院分区：
文献类型：
--
作者：
Fischer, Lindsey R.;Igoudjil, Anissa;Glass, Jonathan D.
运动轴突变性是运动神经元疾病中导致虚弱和肌肉萎缩的关键事件，但人们对此知之甚少。在这里，我们研究了氧化应激介导的缺乏抗氧化酶铜锌超氧化物歧化酶(SOD1)的小鼠的轴突变性。我们在这些小鼠中发现了进行性运动性轴索病变，并显示SOD1(-/-)初级运动神经元在体外延伸短轴突，线粒体密度降低。SOD1(-/-)神经元也表现出线粒体硫氧还蛋白的氧化，但不是胞浆硫氧还蛋白，这表明SOD1的缺失导致了线粒体的优先氧化应激，线粒体是细胞中超氧化物的主要来源。SOD1被广泛认为是超氧化物歧化酶的胞浆异构体，但也存在于线粒体膜间间隙。SOD1在膜间隙中的功能意义尚不清楚。我们使用转基因方法在膜间隙中专门表达SOD1，发现线粒体SOD1足以防止SOD1(-/-)模型中的生化和形态缺陷，并在追踪到12个月大时挽救这些小鼠的运动表型。这些结果表明，线粒体膜间间隙中的SOD1是运动轴突维持的基础，并且在运动轴突变性的发病机制中涉及线粒体部位的氧化损伤。
Motor axon degeneration is a critical but poorly understood event leading to weakness and muscle atrophy in motor neuron diseases. Here, we investigated oxidative stress-mediated axonal degeneration in mice lacking the antioxidant enzyme, Cu,Zn superoxide dismutase (SOD1). We demonstrate a progressive motor axonopathy in these mice and show that Sod1(-/-) primary motor neurons extend short axons in vitro with reduced mitochondrial density. Sod1(-/-) neurons also show oxidation of mitochondrial-but not cytosolic-thioredoxin, suggesting that loss of SOD1 causes preferential oxidative stress in mitochondria, a primary source of superoxide in cells. SOD1 is widely regarded as the cytosolic isoform of superoxide dismutase, but is also found in the mitochondrial intermembrane space. The functional significance of SOD1 in the intermembrane space is unknown. We used a transgenic approach to express SOD1 exclusively in the intermembrane space and found that mitochondrial SOD1 is sufficient to prevent biochemical and morphological defects in the Sod1(-/-) model, and to rescue the motor phenotype of these mice when followed to 12 months of age. These results suggest that SOD1 in the mitochondrial intermembrane space is fundamental for motor axon maintenance, and implicate oxidative damage initiated at mitochondrial sites in the pathogenesis of motor axon degeneration.