Klein Jeffrey A, Longo-Guess Chantal M, Rossmann Marlies P, Seburn Kevin L, Hurd Ronald E, Frankel Wayne N, Bronson Roderick T, Ackerman Susan L
The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA.
Nature. 2002 Sep 26;419(6905):367-74. doi: 10.1038/nature01034.
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.
丑角（Hq）突变小鼠的终末分化小脑和视网膜神经元会进行性退化。我们已确定Hq突变是凋亡诱导因子（Aif）基因中的前病毒插入，导致AIF表达降低约80%。突变的小脑颗粒细胞易受外源性和内源性过氧化物介导的凋亡影响，但可通过AIF表达得到挽救。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作为自由基清除剂发挥作用。与此一致的是，老年Hq突变小鼠中垂死的神经元表现出氧化应激。此外，Hq突变小鼠小脑和视网膜中受氧化应激损伤的神经元在凋亡前重新进入细胞周期。我们的结果提供了一个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与氧化应激之间的直接联系。
