Neuronal death in amyotrophic lateral sclerosis is apoptosis: Possible contribution of a programmed cell death mechanism
Neuronal death in amyotrophic lateral sclerosis is apoptosis: Possible contribution of a programmed cell death mechanism
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DOI：
10.1097/00005072-199905000-00005
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发表时间：
1999-05-01
影响因子：
3.2
通讯作者：
Martin, LJ
中科院分区：
文献类型：
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作者：
Martin, LJ
肌萎缩侧索硬化症 (ALS) 神经退行性变的机制尚不清楚。我们发现 ALS 中的运动神经元变性在结构上类似于细胞凋亡。神经元死亡的进程可分为 3 个连续的阶段：染色质分解、体细胞树突磨损和细胞凋亡。在 ALS 脊髓前角和运动皮层中，DNA 片段化可在原位和凝胶中检测到，并且发生在核小体间，在 DNA 片段化因子 45/40 激活和 caspase-3 活性增加的情况下发生。通过免疫印迹，细胞死亡蛋白的亚细胞分布发生变化，从而促进细胞凋亡。与对照组相比，在 ALS 中选择性脆弱的 CNS 区域中，促凋亡蛋白 Bax 和 Bak 在富含线粒体的膜区室中升高，但在细胞质中降低或不变。相比之下，抗凋亡蛋白 Bcl-2 在 ALS 脆弱区域的线粒体富集膜区室中减少，但在胞质溶胶中增加，而 Bcl-x(L) 水平在两个亚细胞区室中没有变化。免疫共沉淀实验表明，与对照组相比，ALS 运动皮层富含线粒体的膜区室中的 Bax-Bax 相互作用更强，而 ALS 运动皮层膜区室中的 Bax-Bcl-2 相互作用与对照组相比较低。我们得出的结论是，PCD 机制涉及细胞死亡蛋白的细胞质到膜和膜到细胞质的重新分配以及 caspase-3 的激活，参与了 ALS 的发病机制。
The mechanisms for neurodegeneration in amyotrophic lateral sclerosis (ALS) are not understood. We found that motor neuron degeneration in ALS structurally resembles apoptosis. The progression of neuronal death is divisible into 3 sequential stages: chromatolysis, somatodendritic attrition, and apoptosis. In ALS spinal cord anterior horn and motor cortex, DNA fragmentation is detectable in situ and in gels and is internucleosomal, occurring in the presence of DNA fragmentation factor-45/40 activation and increased caspase-3 activity. By immunoblotting, changes occur in the subcellular distribution of cell death proteins that would promote apoptosis. In selectively vulnerable CNS regions in ALS compared with controls, the proapoptotic proteins Bax and Bak are elevated in the mitochondrial-enriched membrane compartment, but are reduced or unchanged in the cytosol. Ln contrast, the antiapoptotic protein Bcl-2 is decreased in the mitochondrial-enriched membrane compartment of vulnerable regions in ALS, but is increased in the cytosol, whereas Bcl-x(L) levels are unchanged in both subcellular compartments. Coimmunoprecipitation experiments showed that Bax-Bax interactions are greater in the mitochondrial-enriched membrane compartment of ALS motor cortex compared with controls, whereas Bax-Bcl-2 interactions are lower in the membrane compartment of ALS motor cortex compared with controls. We conclude that a PCD mechanism, involving cytosol-to-membrane and membrane-to-cytosol redistribution of cell death proteins and caspase-3 activation, participates in the pathogenesis of ALS.