Martin Lee J
Department of Pathology, Division of Neuropathology, Department of Neuroscience, Johns Hopkins University School ofMedicine, Baltimore, MD 21205-2196, USA.
Rev Neurosci. 2007;18(2):115-36. doi: 10.1515/revneuro.2007.18.2.115.
A variety of gene mutations can cause familial forms of Parkinson's disease (PD) or amyotrophic lateral sclerosis (ALS). Mutations in the synaptic protein alpha-synuclein (alpha-Syn) cause PD. Mutations in the antioxidant enzyme superoxide dismutase-1 (SOD1) cause ALS. The mechanisms of human mutant a-Syn and SOD1 toxicity to neurons are not known. Transgenic (tg) mice expressing human mutant alpha-Syn or SOD1 develop profound fatal neurologic disease characterized by progressive motor deficits, paralysis, and neurodegeneration. Ala-53-->Thr (A53T)-mutant alpha-Syn and Gly-93-->Ala (G93A)-mutant SOD1 tg mice develop prominent mitochondrial abnormalities. Interestingly, although nigral neurons in A53T mice are relatively preserved, spinal motor neurons (MNs) undergo profound degeneration. In A53T mice, mitochondria degenerate in neurons, and complex IV activity is reduced. Furthermore, mitochondria in neurons develop DNA breaks and have p53 targeted to the outer membrane. Nitrated a-Syn accumulates in degenerating MNs in A53T mice. mSOD1 mouse MNs accumulate mitochondria from the axon terminals and generate higher levels of reactive oxygen/nitrogen species than MNs in control mice. mSOD1 mouse MNs accumulate DNA single-strand breaks prior to double-strand breaks occurring in nuclear and mitochondrial DNA. Nitrated and aggregated cytochrome c oxidase subunit-I and nitrated SOD2 accumulate in mSOD1 mouse spinal cord. Mitochondria in mSOD1 mouse MNs accumulate NADPH diaphorase and inducible NOS (iNOS)-like immunoreactivity, and iNOS gene deletion significantly extends the lifespan of G93A-mSOD1 mice. Mitochondrial changes develop long before symptoms emerge. These experiments reveal that mitochondrial nitrative stress and perturbations in mitochondrial trafficking may be antecedents of neuronal cell death in animal models of PD and ALS.
多种基因突变可导致帕金森病（PD）或肌萎缩侧索硬化症（ALS）的家族性形式。突触蛋白α-突触核蛋白（α-Syn）的突变会导致帕金森病。抗氧化酶超氧化物歧化酶1（SOD1）的突变会导致肌萎缩侧索硬化症。人类突变型α-Syn和SOD1对神经元产生毒性的机制尚不清楚。表达人类突变型α-Syn或SOD1的转基因（tg）小鼠会发展出严重的致命性神经疾病，其特征为进行性运动功能障碍、瘫痪和神经退行性变。丙氨酸-53→苏氨酸（A53T）突变型α-Syn和甘氨酸-93→丙氨酸（G93A）突变型SOD1转基因小鼠会出现明显的线粒体异常。有趣的是，尽管A53T小鼠中的黑质神经元相对保留，但脊髓运动神经元（MNs）却会发生严重退化。在A53T小鼠中，神经元中的线粒体退化，复合物IV活性降低。此外，神经元中的线粒体出现DNA断裂，并且p53定位于外膜。硝化的α-Syn在A53T小鼠退化的MNs中积累。mSOD1小鼠的MNs从轴突末端积累线粒体，并比对照小鼠的MNs产生更高水平的活性氧/氮物种。mSOD1小鼠的MNs在核DNA和线粒体DNA出现双链断裂之前就积累了DNA单链断裂。硝化和聚集的细胞色素c氧化酶亚基-I以及硝化的SOD2在mSOD1小鼠脊髓中积累。mSOD1小鼠MNs中的线粒体积累了NADPH黄递酶和诱导型一氧化氮合酶（iNOS）样免疫反应性，并且iNOS基因缺失显著延长了G93A-mSOD1小鼠的寿命。线粒体变化早在症状出现之前就已发生。这些实验表明，线粒体硝化应激和线粒体运输紊乱可能是帕金森病和肌萎缩侧索硬化症动物模型中神经元细胞死亡的先兆。
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