Txn1 mutation causes epilepsy associated with vacuolar degeneration in the midbrain

Thioredoxin (TXN), 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 TXN in the central nervous system (CNS) is largely unknown. A phenotype-driven study of N -ethyl- N -nitrosourea-mutated rats with running seizures at around five-week of age revealed the relevance of Txn1 mutations to CNS disorders. Genetic mapping identified Txn1 -F54L in epileptic rats. The insulin-reducing activity of Txn1 -F54L rats was approximately one-third that of the wild-type. 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 oligodendrocyte cell death. Neurons in Txn1 -F54L rats showed morphological changes in the mitochondria. Vacuolar degeneration began at three weeks of age, and spontaneous repair began at seven weeks; a dramatic change from cell death to repair occurred in the midbrain during a restricted period. In conclusion, Txn1 is essential for the development of the midbrain in juvenile rats. ### Competing Interest Statement The authors have declared no competing interest. * CNS : central nervous system; WT : wild type; ROS : reactive oxygen species NADPH : Nicotinamide adenine dinucleotide phosphate; NOX : NADPH oxidases; ENU : N-ethyl-N-nitrosourea SOD : superoxide dismutase; CAT : catalase; HD : Huntington’s disease; ALS : amyotrophic lateral sclerosis; MS : multiple sclerosis; GSH : Glutathione; GPx : glutathione peroxidase; Prdx : peroxiredoxin Txn : thioredoxin; MRI : magnetic resonance imaging; 8-OHdG : 8-hydroxy-2’-deoxyguanosine; 4-HNE : 4-hydroxynonenal TUNEL : Terminal deoxynucleotidyl transferase-mediated dUTP Nick End Labeling PBS : phosphate-buffered saline; HE : hematoxylin and eosin; KB : Klüver-Barrera DAB : 3,3’-diaminobenzidine; IHC : immunohistochemistry; GFAP : glial fibrillary acidic protein; GAPDH : Glyceraldehyde 3-phosphate dehydrogenase TEM : Transmission electron microscope;