The harlequin mouse mutation down-regulates apoptosis-inducing factor
The harlequin mouse mutation down-regulates apoptosis-inducing factor
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DOI：
10.1038/nature01034
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发表时间：
2002-09-26
期刊：
影响因子：
64.8
通讯作者：
Ackerman, SL
中科院分区：
文献类型：
--
作者：
Klein, JA;Longo-Guess, CM;Ackerman, SL
Harlequin（Hq）突变小鼠具有终末分化的小脑和视网膜神经元的进行性变性。我们已经确定了Hq突变作为一个前病毒插入的骨化诱导因子（AIF）基因，导致约80%的AIF表达减少。突变的小脑颗粒细胞对外源性和内源性过氧化物介导的凋亡敏感，但可以通过AIF表达来拯救。野生型颗粒细胞中AIF的过表达进一步降低了过氧化物介导的细胞死亡，表明AIF充当自由基清除剂。在协议中，衰老的Hq突变小鼠中垂死的神经元显示氧化应激。此外，Hq突变小鼠小脑和视网膜中的氧化应激损伤的神经元在经历凋亡之前重新进入细胞周期。我们的研究结果提供了氧化应激介导的神经退行性变的遗传模型，并证明了衰老中枢神经系统中细胞周期重新进入和氧化应激之间的直接联系。
Harlequin (Hq) mutant mice have progressive degeneration of terminally differentiated cerebellar and retinal neurons. We have identified the Hq mutation as a proviral insertion in the apoptosis-inducing factor (Aif) gene, causing about an 80% reduction in AIF expression. Mutant cerebellar granule cells are susceptible to exogenous and endogenous peroxide-mediated apoptosis, but can be rescued by AIF expression. Overexpression of AIF in wild-type granule cells further decreases peroxide-mediated cell death, suggesting that AIF serves as a free radical scavenger. In agreement, dying neurons in aged Hq mutant mice show oxidative stress. In addition, neurons damaged by oxidative stress in both the cerebellum and retina of Hq mutant mice re-enter the cell cycle before undergoing apoptosis. Our results provide a genetic model of oxidative stress-mediated neurodegeneration and demonstrate a direct connection between cell cycle re-entry and oxidative stress in the ageing central nervous system.