Sarlette Alexander, Krampfl Klaus, Grothe Claudia, Neuhoff Nils von, Dengler Reinhard, Petri Susanne
Department of Neurology Neuroanatomy , and Institute for Cell and Molecular Pathology , Hannover Medical School, Hannover, Germany.
J Neuropathol Exp Neurol. 2008 Nov;67(11):1055-62. doi: 10.1097/NEN.0b013e31818b4906.
Oxidative stress and inflammation are important pathogenetic mechanisms in amyotrophic lateral sclerosis (ALS). Nuclear erythroid 2-related factor 2 (Nrf2) is a basic region leucine-zipper transcription factor that binds to the antioxidant response element, thereby regulating the expression of many genes that are involved in cellular antioxidant and anti-inflammatory defense. Under normal conditions, Nrf2 activation is inhibited by Kelch-like ECH-associated protein 1 (Keap1). We investigated the potential involvement of the Nrf2/antioxidant response element signaling pathway in the selective degeneration of motor neurons in ALS. Nrf2 and Keap1 expression was analyzed in primary motor cortex and spinal cord postmortem tissue samples from ALS patients and controls by in situ hybridization histochemistry, quantitative real-time polymerase chain reaction, immunohistochemistry, and Western blot analysis. In ALS samples, there was a reduction of Nrf2 mRNA and protein expression in neurons, whereas Keap1 mRNA expression was increased in the motor cortex. These results suggest that alterations in this signaling cascade occur in motor neurons in ALS and that they may contribute to chronic motor neuron degeneration.
氧化应激和炎症是肌萎缩侧索硬化症（ALS）重要的发病机制。核红细胞2相关因子2（Nrf2）是一种碱性区域亮氨酸拉链转录因子，它与抗氧化反应元件结合，从而调节许多参与细胞抗氧化和抗炎防御的基因的表达。在正常情况下，Nrf2的激活受到 Kelch样ECH相关蛋白1（Keap1）的抑制。我们研究了Nrf2/抗氧化反应元件信号通路在ALS运动神经元选择性变性中的潜在作用。通过原位杂交组织化学、定量实时聚合酶链反应、免疫组织化学和蛋白质印迹分析，对ALS患者和对照组的原发性运动皮层和脊髓死后组织样本中的Nrf2和Keap1表达进行了分析。在ALS样本中，神经元中Nrf2 mRNA和蛋白表达减少，而运动皮层中Keap1 mRNA表达增加。这些结果表明，该信号级联反应的改变发生在ALS的运动神经元中，并且可能导致慢性运动神经元变性。
