Ohmori Iori, Ouchida Mamoru, Imai Hirohiko, Ishida Saeko, Toyokuni Shinya, Mashimo Tomoji
Section of Developmental Physiology and Pathology, Faculty of Education, Okayama University, Tsushima 3-chome 1-1, Kita-ku, Okayama 700-8530, Japan; Department of Child Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Shikatacho 2-Chome 5-1, Kita-Ku, Okayama 700-8558, Japan.
Department of Molecular Oncology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Shikatacho 2-Chome 5-1, Kita-Ku, Okayama 700-8558, Japan.
Neurobiol Dis. 2022 Dec;175:105921. doi: 10.1016/j.nbd.2022.105921. Epub 2022 Nov 11.
Thioredoxin, encoded by Txn1, acts as a critical antioxidant in the defense against oxidative stress by regulating the dithiol/disulfide balance of interacting proteins. The role of thioredoxin in the central nervous system (CNS) is largely unknown. A phenotype-driven study of N-ethyl-N-nitrosourea-mutated rats with wild-running seizures revealed the importance of Txn1 mutations in CNS degeneration. Genetic mapping identified Txn1-F54L in the epileptic rats. The insulin-reducing activity of Txn1-F54L was approximately one-third of that of the wild-type (WT). Bilateral symmetrical vacuolar degeneration in the midbrain, mainly in the thalamus and the inferior colliculus, was observed in the Txn1-F54L rats. The lesions displayed neuronal and oligodendrocytic cell death. Neurons in Txn1-F54L rats showed morphological changes in the mitochondria. Vacuolar degeneration peaked at five weeks of age, and spontaneous repair began at seven weeks. The TUNEL assay showed that fibroblasts derived from homozygotes were susceptible to cell death under oxidative stress. In five-week-old WT rats, energy metabolism in the thalamus was significantly higher than that in the cerebral cortex. In conclusion, in juvenile rats, Txn1 seems to play an essential role in reducing oxidative stress in the midbrains with high energy metabolism.
由Txn1编码的硫氧还蛋白通过调节相互作用蛋白的二硫醇/二硫化物平衡，在抵御氧化应激中发挥关键的抗氧化作用。硫氧还蛋白在中枢神经系统（CNS）中的作用在很大程度上尚不清楚。一项对患有狂奔性癫痫的N-乙基-N-亚硝基脲突变大鼠进行的表型驱动研究揭示了Txn1突变在CNS退化中的重要性。基因定位在癫痫大鼠中确定了Txn1-F54L。Txn1-F54L的胰岛素还原活性约为野生型（WT）的三分之一。在Txn1-F54L大鼠中观察到中脑双侧对称性空泡变性，主要位于丘脑和下丘。病变显示神经元和少突胶质细胞死亡。Txn1-F54L大鼠的神经元线粒体出现形态变化。空泡变性在5周龄时达到峰值，7周龄时开始自发修复。TUNEL检测显示，来自纯合子的成纤维细胞在氧化应激下易发生细胞死亡。在5周龄的WT大鼠中，丘脑的能量代谢显著高于大脑皮层。总之，在幼年大鼠中，Txn1似乎在降低高能量代谢中脑的氧化应激方面发挥着重要作用。
