Attenuation of MPTP‐induced neurotoxicity and locomotor dysfunction in Nucling‐deficient mice via suppression of the apoptosome pathway
Attenuation of MPTP‐induced neurotoxicity and locomotor dysfunction in Nucling‐deficient mice via suppression of the apoptosome pathway
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DOI：
10.1111/j.1471-4159.2006.03833.x
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发表时间：
2006-05
影响因子：
4.7
通讯作者：
Xichuan Teng;T. Sakai;Li Liu;Rika Sakai;R. Kaji;K. Fukui
中科院分区：
文献类型：
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作者：
Xichuan Teng;T. Sakai;Li Liu;Rika Sakai;R. Kaji;K. Fukui
1‐甲基‐4‐苯基‐1,2,3,6‐四氢吡啶（MPTP）‐诱导的神经毒性是研究帕金森病（PD）发病机制最常用的实验模型之一。尽管MPTP诱导细胞死亡的生化机制尚不清楚，但已经发现线粒体凋亡信号通路在MPTP的神经毒性中起重要作用。成核是一种新型的凋亡相关分子，对细胞色素c、凋亡蛋白酶激活因子1 （Apaf‐1）、促凋亡caspase‐9凋亡诱导和促凋亡应激后的caspase‐9活化至关重要。在这里，我们发现用MPTP治疗的成核缺陷小鼠在开放场试验中没有表现出运动功能障碍。成核缺陷小鼠的黑质多巴胺能神经元能够抵抗神经毒素MPTP的损伤作用。在MPTP处理的成核缺陷小鼠中，凋亡蛋白的上调表达被减弱。这些结果表明成核在MPTP诱导的神经元变性中起重要作用，并提示抑制成核可能对PD神经变性的治疗有益。
1‐Methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced neurotoxicity is one of the experimental models most commonly used to study the pathogenesis of Parkinson's disease (PD). Although the biochemical mechanisms underlying the cell death induced by MPTP remain to be clarified, it has been found that the mitochondrial apoptotic signaling pathway plays an important role in the neurotoxicity of MPTP. Nucling is a novel type of apoptosis‐associated molecule, essential for cytochrome c, apoptosis protease activating factor 1 (Apaf‐1), pro‐caspase‐9 apoptosome induction and caspase‐9 activation following pro‐apoptotic stress. Here we found that Nucling‐deficient mice treated with MPTP did not exhibit locomotor dysfunction in an open‐field test. The substantia nigra dopaminergic neurons of Nucling‐deficient mice were resistant to the damaging effects of the neurotoxin MPTP. Up‐regulated expression of apoptosome was attenuated in Nucling‐deficient mice treated with MPTP. These results indicate an important role for Nucling in MPTP‐induced neuronal degeneration and suggest that the suppression of Nucling would be of therapeutic benefit for the treatment of neurodegeneration in PD.