Department of Neurology, College of Medicine, Yonsei University, Republic of Korea; Department of Anatomy and Brain Korea 21 Project for Medical Science, Yonsei University, College of Medicine, Seoul 120-752, Republic of Korea.
Biochem Biophys Res Commun. 2013 Nov 15;441(2):280-5. doi: 10.1016/j.bbrc.2013.08.103. Epub 2013 Sep 8.
Apoptosis signal-regulating kinase-1 (ASK1), an early signaling element in the cell death pathway, has been suggested to participate in the pathology of neurodegenerative diseases, which may be associated with environmental factors that impact the diseases. Although it is not entirely elucidated, 3-nitropropionic acid (3-NP) provokes mitochondrial dysfunction and selectively forms striatal lesions similar to those found in Huntington's disease. The current study investigated whether ASK1 is involved in striatal pathology following chronic systemic infusion of 3-NP. The results show that ASK1 acts as a primary mediator of there active oxygen species (ROS) cell death signal cascade in the 3-NP-damaged striatal region by disrupting the positive feedback cycle. In 3-NP-infused striatal lesions, ROS increased ASK1. Superoxide dismutase transgenic (SOD-tg) mice reduced ASK1by scavenging ROS, and reduction of ASK1leads to a reduction in cell death. However, ASK1 down-regulation in 3-NP infusion mice also decreased striatal cell death without scavenging ROS. In contrast decreasing cell death by si-ASK1 treatment along with 3-NP in both SOD tg and wild-type mice (wt), cell death rebounded when ASK1 peptide was added to SOD tg mice. The present study suggests that ROS-inducing ASK1 may be an important step in the pathogenesis of 3-NP infused striatal lesions in murine brains.
凋亡信号调节激酶 1（ASK1）作为细胞死亡途径中的早期信号元件，被认为参与神经退行性疾病的病理学过程，这可能与影响疾病的环境因素有关。虽然其确切机制尚未完全阐明，但 3-硝基丙酸（3-NP）可诱发线粒体功能障碍，并选择性地形成类似于亨廷顿病的纹状体损伤。本研究旨在探讨慢性系统性 3-NP 输注后 ASK1 是否参与纹状体病变。结果表明，ASK1 通过破坏正反馈循环，作为 3-NP 损伤纹状体区域活性氧（ROS）细胞死亡信号级联反应的主要介质发挥作用。在 3-NP 输注的纹状体损伤中，ROS 增加了 ASK1 的表达。超氧化物歧化酶转基因（SOD-tg）小鼠通过清除 ROS 减少了 ASK1，而 ASK1 的减少则导致细胞死亡减少。然而，在 3-NP 输注小鼠中下调 ASK1 也可减少纹状体细胞死亡，而无需清除 ROS。相反，在 SOD-tg 和野生型（wt）小鼠中，用 si-ASK1 处理与 3-NP 共同降低细胞死亡时，当将 ASK1 肽添加到 SOD-tg 小鼠中时，细胞死亡又会反弹。本研究表明，ROS 诱导的 ASK1 可能是 3-NP 诱导的鼠脑纹状体损伤发病机制中的重要步骤。
