Early vacuolization and mitochondrial damage in motor neurons of FALS mice are not associated with apoptosis or with changes in cytochrome oxidase histochemical reactivity
Early vacuolization and mitochondrial damage in motor neurons of FALS mice are not associated with apoptosis or with changes in cytochrome oxidase histochemical reactivity
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DOI：
10.1016/s0022-510x(01)00627-x
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发表时间：
2001-10-15
影响因子：
4.4
通讯作者：
De Biasi, S
中科院分区：
文献类型：
--
作者：
Bendotti, C;Calvaresi, N;De Biasi, S
突变型超氧化物歧化酶（SOD 1）在转基因小鼠中的过度表达导致脊髓中进行性运动神经元变性，类似于人类肌萎缩侧索硬化症（ALS）。在携带SOD 1的G93 A突变的转基因C57 BL/6小鼠中，在疾病的不同阶段对运动神经元的超微结构分析显示，在约2周龄时，比疾病的初始症状早得多，细胞质中出现微空泡，线粒体明显肿胀。在这些运动神经元中从未观察到具有凋亡形态的细胞核。在发病前，在膈神经运动轴突的远端部分和坐骨神经的大轴突中也观察到Swedish线粒体，但在骨骼肌和坐骨神经的小轴突中未观察到线粒体的改变。此外，我们发现，即使在疾病的晚期，转基因小鼠的运动神经元细胞色素氧化酶的组织化学反应性也没有明显的变化，这表明尽管线粒体发生了改变，但这些细胞中的部分神经元活性可能仍得以维持。在转基因小鼠的运动神经元中，人SOD 1的免疫反应性在空泡周围很高，但没有观察到胞质内SOD 1聚集体。我们的数据表明，线粒体肿胀可能是一个重要的因素触发级联导致进行性运动神经元死亡。线粒体通透性转换孔的激活可能通过兴奋性毒性或其他神经毒性刺激参与该过程。(C)2001 Elsevier Science B. V.保留所有权利。
Overexpression of mutated superoxide dismutase (SOD1) in transgenic mice causes a progressive motor neuron degeneration in the spinal cord similar to that in human amyotrophic lateral sclerosis (ALS). Ultrastructural analysis of motor neurons at different stages of the disease in transgenic C57BL/6 mice carrying the G93A mutation of SOD1 showed, at about 2 weeks of age, much earlier than the initial symptoms of the disease, microvacuoles in the cytoplasm, with marked swelling of the mitochondria. Nuclei with an apoptotic morphology were never observed in these motor neurons. Swollen mitochondria were also seen in the distal part of motor axons of phrenic nerves and in the large axons of sciatic nerves before the onset of the disease, but no mitochondrial alterations were seen in skeletal muscles or in the small sciatic nerve axons. Moreover, we found no apparent changes in the histochemical reactivity of cytochrome oxidase in motor neurons of transgenic mice even at the advanced sta-e of the disease, suggesting that partial neuronal activity in these cells may be maintained despite the altered mitochondria. Immunoreactivity for human SOD1 was high around vacuoles in the motor neurons of transgenic mice but no cytoplasmic intracellular SOD1 aggregates were observed. Our data indicate that mitochondrial swelling may be an important factor triggering the cascade leading to progressive motor neuron death. Activation of the mitochondrial permeability transition pore may be involved in this process, through excitotoxicity or other neurotoxic stimuli. (C) 2001 Elsevier Science B.V. All rights reserved.