Apoptosis inducing factor mediates caspase-independent 1-methyl-4-phenylpyridinium toxicity in dopaminergic cells
Apoptosis inducing factor mediates caspase-independent 1-methyl-4-phenylpyridinium toxicity in dopaminergic cells
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DOI：
10.1111/j.1471-4159.2005.03329.x
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发表时间：
2005-09-01
影响因子：
4.7
通讯作者：
Chen, J
中科院分区：
文献类型：
--
作者：
Chu, CT;Zhu, J;Chen, J
帕金森氏病是一种以中脑多巴胺能神经元丧失为特征的衰弱神经退行性疾病。这些神经元对神经毒素1-甲基-4-苯基吡啶(MPP+)特别敏感，MPP+是1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)的活性代谢物，可导致人类、猴子和啮齿动物的帕金森综合征。尽管细胞凋亡与MPTP/MPP+毒性有关，但最近的一些研究挑战了caspase依赖的细胞凋亡在多巴胺能神经元中的作用。利用中脑来源的MN9D多巴胺能细胞系，我们发现MPP+处理导致了一种活跃的细胞死亡形式，这不能通过caspase抑制剂或过度表达显性的凋亡蛋白酶激活因子1/caspase-9的负性抑制物来阻止。凋亡诱导因子(AIF)是一种线粒体蛋白，在其移位到细胞核后可能介导caspase不依赖于caspase的调节性细胞死亡。我们发现MPP+处理引起AIF的核移位，并伴随着大规模的DNA断裂。为了确定AIF在MPP+毒性中的作用，我们构建了针对AIF的短发夹状序列的DNA载体。通过RNA干扰降低AIF的表达抑制了DNA的大规模断裂，并对MPP+毒性具有显著的保护作用。对小鼠中脑原代培养的研究进一步支持了AIF在MPP+处理的多巴胺能神经元中caspase非依赖性细胞死亡中的作用。
Parkinson's disease is a debilitating neurodegenerative disease characterized by loss of midbrain dopaminergic neurons. These neurons are particularly sensitive to the neurotoxin 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which causes parkinsonian syndromes in humans, monkeys and rodents. Although apoptotic cell death has been implicated in MPTP/MPP+ toxicity, several recent studies have challenged the role of caspase-dependent apoptosis in dopaminergic neurons. Using the midbrain-derived MN9D dopaminergic cell line, we found that MPP+ treatment resulted in an active form of cell death that could not be prevented by caspase inhibitors or over-expression of a dominant negative inhibitor of apoptotic protease activating factor 1/caspase-9. Apoptosis inducing factor (AIF) is a mitochondrial protein that may mediate caspase-independent forms of regulated cell death following its translocation to the nucleus. We found that MPP+ treatment elicited nuclear translocation of AIF accompanied by large-scale DNA fragmentation. To establish the role of AIF in MPP+ toxicity, we constructed a DNA vector encoding a short hairpin sequence targeted against AIF. Reduction of AIF expression by RNA interference inhibited large-scale DNA fragmentation and conferred significant protection against MPP+ toxicity. Studies of primary mouse midbrain cultures further supported a role for AIF in caspase-independent cell death in MPP+-treated dopaminergic neurons.