Department of Anatomy, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Pokfulam, Hong Kong, China; Research Center of Reproduction, Development and Growth, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Pokfulam, Hong Kong, China.
Neuropathol Appl Neurobiol. 2014 Jun;40(4):435-51. doi: 10.1111/nan.12071.
Apurinic/apyrimidinic endonuclease 1 (APE1) is an intermediate enzyme in base excision repair which is important for removing damaged nucleotides under normal and pathological conditions. Accumulation of damaged bases causes genome instability and jeopardizes cell survival. Our study is to examine APE1 regulation under oxidative stress in spinal motor neurones which are vulnerable to oxidative insult.
We challenged the motor neurone-like cell line NSC-34 with hydrogen peroxide and delineated APE1 function by applying various inhibitors. We also examined the expression of APE1 in spinal motor neurones after spinal root avulsion in adult rats.
We showed that hydrogen peroxide induced APE1 down-regulation and cell death in a differentiated motor neurone-like cell line. Inhibiting the two functional domains of APE1, namely, DNA repair and redox domains potentiated hydrogen peroxide induced cell death. We further showed that p53 phosphorylation early after hydrogen peroxide treatment might contribute to the down-regulation of APE1. Our in vivo results similarly showed that APE1 was down-regulated after root avulsion injury in spinal motor neurones. Delay of motor neurone death suggested that APE1 might not cause immediate cell death but render motor neurones vulnerable to further oxidative insults.
We conclude that spinal motor neurones down-regulate APE1 upon oxidative stress. This property renders motor neurones susceptible to continuous challenge of oxidative stress in pathological conditions.
脱嘌呤/脱嘧啶核酸内切酶 1（APE1）是碱基切除修复中的一种中间酶，对于在正常和病理条件下清除受损核苷酸非常重要。受损碱基的积累会导致基因组不稳定，并危及细胞存活。我们的研究旨在研究氧化应激下脊髓运动神经元中 APE1 的调节，因为这些神经元容易受到氧化损伤。
我们用过氧化氢挑战类似于运动神经元的 NSC-34 细胞系，并通过应用各种抑制剂来描绘 APE1 的功能。我们还检查了成年大鼠脊神经根切断后脊髓运动神经元中 APE1 的表达。
我们表明，过氧化氢诱导分化的类似于运动神经元的细胞系中 APE1 的下调和细胞死亡。抑制 APE1 的两个功能域，即 DNA 修复和氧化还原域，增强了过氧化氢诱导的细胞死亡。我们进一步表明，过氧化氢处理后早期的 p53 磷酸化可能导致 APE1 的下调。我们的体内结果同样表明，脊神经根切断损伤后脊髓运动神经元中 APE1 下调。运动神经元死亡的延迟表明 APE1 可能不会立即导致细胞死亡，而是使运动神经元易受进一步氧化应激的影响。
我们得出结论，脊髓运动神经元在氧化应激下下调 APE1。这种特性使运动神经元容易受到病理条件下持续氧化应激的挑战。
