Thioredoxin deficiency increases oxidative stress and causes bilateral symmetrical degeneration in rat midbrain

Iori Ohmori; Mamoru Ouchida; Hirohiko Imai; Saeko Ishida; Shinya Toyokuni; Tomoji Mashimo

doi:10.1016/j.nbd.2022.105921

Thioredoxin deficiency increases oxidative stress and causes bilateral symmetrical degeneration in rat midbrain

Neurobiol Dis. 2022 Dec:175:105921. doi: 10.1016/j.nbd.2022.105921. Epub 2022 Nov 11.

Authors

Iori Ohmori¹, Mamoru Ouchida², Hirohiko Imai³, Saeko Ishida⁴, Shinya Toyokuni⁵, Tomoji Mashimo⁶

Affiliations

¹ 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. Electronic address: iori@md.okayama-u.ac.jp.
² 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. Electronic address: ouchidam@md.okayama-u.ac.jp.
³ Department of Systems Science, Kyoto University Graduate School of Informatics, Yoshida-Honmachi, Sakyo-ward, Kyoto 606-8501, Japan. Electronic address: imai@sys.i.kyoto-u.ac.jp.
⁴ Division of Animal Genetics, Laboratory Animal Research Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. Electronic address: saeishida@ims.u-tokyo.ac.jp.
⁵ Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya 466-8550, Japan. Electronic address: toyokuni@med.nagoya-u.ac.jp.
⁶ Division of Animal Genetics, Laboratory Animal Research Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. Electronic address: mashimo@ims.u-tokyo.ac.jp.

PMID: 36372289
DOI: 10.1016/j.nbd.2022.105921

Abstract

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.

Keywords: Epilepsy; Mitochondria; Oxidative stress; Thioredoxin; Txn1; Vacuolar degeneration.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antioxidants
Mesencephalon / metabolism
Oxidation-Reduction
Oxidative Stress* / physiology
Rats
Thioredoxins* / genetics
Thioredoxins* / metabolism

Substances

Thioredoxins
Antioxidants