Laboratory of Molecular Iron Metabolism, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei Province, 050024, China.
Laboratory of Molecular Iron Metabolism, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei Province, 050024, China; Department of Neurology, Hebei Medical University, Shijiazhuang, Hebei Province, 050017, China.
Free Radic Biol Med. 2021 Jan;162:592-602. doi: 10.1016/j.freeradbiomed.2020.11.019. Epub 2020 Nov 26.
The transcription factor NF-E2-related factor 2 (Nrf2) is a central regulator of cellular antioxidant and detoxification response. The association between Nrf2 activity and iron-related oxidative stress in neurodegenerative diseases has been studied, and Nrf2 was found to transcriptionally regulate the expression of iron transporters and ferroptosis-related factors. However, the role of Nrf2 in age-related motor dysfunction and its link to iron metabolism dysregulation in brain have not been fully elucidated. In this study, with different ages of Nrf2 knockout (KO) and wild type (WT) mice, we investigated the effects of Nrf2 deficiency on brain oxidative stress, iron metabolism and the motor coordination ability of mice. In contrast to the predicted neuroprotective role of Nrf2 in oxidative stress-related diseases, we found that Nrf2 KO remarkably improved the motor coordination of aged mice, which was associated with the reduced ROS level and decreased apoptosis of dopaminergic neurons in substantia nigra (SN) of 18-month-old Nrf2 KO mice. With high-iron and Parkinson's disease (PD) mouse models, we revealed that Nrf2 KO prevented the deposition of brain iron, particularly in SN and striatum, which may subsequently delay motor dysfunction in aged mice. The regulation of Nrf2 KO on brain iron metabolism was likely mediated by decreasing the ferroportin 1 (FPN1) level on brain microvascular endothelial cells, thus hindering the process of iron entry into the brain. Nrf2 may be a potential therapeutic target in age-related motor dysfunction diseases for its role in regulating brain iron homeostasis.
转录因子 NF-E2 相关因子 2（Nrf2）是细胞抗氧化和解毒反应的重要调节剂。已经研究了 Nrf2 活性与神经退行性疾病中铁相关氧化应激之间的关联，并且发现 Nrf2 转录调节铁转运体和铁死亡相关因子的表达。然而，Nrf2 在与年龄相关的运动功能障碍中的作用及其与大脑中铁代谢失调的关系尚未完全阐明。在这项研究中，我们使用不同年龄的 Nrf2 敲除（KO）和野生型（WT）小鼠，研究了 Nrf2 缺乏对大脑氧化应激、铁代谢和小鼠运动协调能力的影响。与 Nrf2 在氧化应激相关疾病中具有神经保护作用的预期相反，我们发现 Nrf2 KO 显著改善了老年小鼠的运动协调能力，这与 18 个月大的 Nrf2 KO 小鼠黑质（SN）中 ROS 水平降低和多巴胺能神经元凋亡减少有关。通过高铁和帕金森病（PD）小鼠模型，我们揭示了 Nrf2 KO 可防止大脑中铁的沉积，特别是在 SN 和纹状体中，这可能随后延缓老年小鼠的运动功能障碍。Nrf2 KO 对大脑铁代谢的调节可能是通过降低脑微血管内皮细胞上的铁蛋白 1（FPN1）水平来介导的，从而阻止铁进入大脑的过程。Nrf2 可能是与年龄相关的运动功能障碍疾病的潜在治疗靶点，因为它在调节大脑铁平衡方面发挥作用。
