Minn Yangki, Cho Kyoung-Joo, Kim Hyun-Woo, Kim Hyun-Jeong, Suk Seung-Han, Lee Byung I, Kim Gyung W
Hangang Sacred Heart Hospital, Department of Neurology, Hallym University, South Korea.
Neurosci Lett. 2008 Jan 10;430(2):142-6. doi: 10.1016/j.neulet.2007.10.042. Epub 2007 Nov 6.
The mitochondrial toxin, 3-nitropropionic acid (3-NP), produces age-dependent oxidative stress and selective striatal damage, which may simulate Huntington's disease starting in middle age. Recent reports showed that apoptosis signal-regulating kinase 1 (Ask1) activated by oxidative stress triggers a cell death signaling pathway. 3-NP was injected to the striatum in C57BL/6J mice. We have confirmed that striatal lesion volume and DNA fragmentation were age-dependent after 3-NP treatment. In the non-injured striatum of the middle-aged group, the protein levels of Ask1 and its active form, phosphorylated Ask1 (pAsk1), were significantly higher than in the young group. Ask1 increased more in the 3-NP injured striatum of the middle-aged group than in the non-injured striatum, and subsequently the activity of pAsk1 was significantly higher than in the young group. However, middle-aged SOD1Tg mice showed significant reductions of Ask1 and pAsk1 in the injured and the non-injured striatum compared to the middle-aged group. In particular, apoptosis signal transduction and cell death were significantly inhibited by the reduction of Ask1 expression using siRNA. Present results suggest that age-related upregulation of Ask1 and oxidative stress may mediate age-dependent striatal vulnerability to 3-NP.
线粒体毒素3-硝基丙酸（3-NP）会产生年龄依赖性氧化应激和选择性纹状体损伤，这可能模拟中年起病的亨廷顿舞蹈病。最近的报告显示，由氧化应激激活的凋亡信号调节激酶1（Ask1）触发细胞死亡信号通路。将3-NP注射到C57BL/6J小鼠的纹状体中。我们已经证实，3-NP处理后纹状体损伤体积和DNA片段化具有年龄依赖性。在中年组未受损的纹状体中，Ask1及其活性形式磷酸化Ask1（pAsk1）的蛋白质水平显著高于年轻组。Ask1在中年组3-NP损伤的纹状体中比在未受损的纹状体中增加得更多，随后pAsk1的活性显著高于年轻组。然而，与中年组相比，中年SOD1Tg小鼠在受损和未受损的纹状体中Ask1和pAsk1均显著降低。特别是，使用小干扰RNA降低Ask1表达可显著抑制凋亡信号转导和细胞死亡。目前的结果表明，Ask1与年龄相关的上调和氧化应激可能介导年龄依赖性纹状体对3-NP的易损性。
