Biology subjects

Ohmori, I.

Publications and source records attributed to Ohmori, I..

3 recordsLinked to original sources

bioRxiv2023

Txn1 mutation is a monogenic cause of chronic kidney disease associated with mitochondrial dysfunction in rats

Oxidative stress plays a significant role in the progression of chronic kidney disease. Thioredoxin 1 (Txn1) is one of the enzymatic antioxidants to regulate redox balance. However, the molecular mechanisms by Txn1 affects renal homeostasis remain unclear. This study aimed at elucidating the pathophysiology of Txn1 mutations in renal function. We used rats with the Txn1-F54L mutation generated by N-ethyl-N-nitrosourea mutagenesis. Laboratory tests and pathological examinations were performed in wild-type (WT) rats and in rats with heterozygous and homozygous Txn1-F54L mutations. We performed RNA-seq analysis of the WT and homozygotes. To confirm phenotypic reproducibility, the Txn1-F54L mutation was generated in rats with different genetic backgrounds using CRISPR/Cas9 genome editing technology. Txn1-F54L mutant rats exhibited progressive albuminuria, hypoalbuminemia, hypercholesterolemia, and hypertension. Renal pathology revealed marked nephrosclerosis, tubular dilatation, interstitial fibrosis, and decreased number of mitochondria, mainly in the paroxysmal tubules. We confirmed a similar phenotype of chronic kidney disease (CKD) in different rat strains. RNA-seq showed the downregulation of mitochondria-related genes and significant upregulation of genes associated with inflammation, pyroptosis, apoptosis, and necroptosis in mutant rats. Our results show that the Txn1 mutation is a monogenic cause of CKD termination. The underlying pathology involves several regulated cell-death pathways. Thus, our study provides a new animal model of oxidative stress-induced CKD. Txn1-F54L mutant rats will aid in developing therapeutic strategies for CKD. Translational StatementWe found that the deficiency of thioredoxin (Txn1), which regulates oxidative stress, spontaneously caused chronic kidney disease (CKD) in rats. The Txn1-F54L (Adem) rat is a new model of CKD with complications such as anemia, hypertension, and cardiovascular disease. Renal pathology revealed nephrosclerosis, interstitial fibrosis, and mitochondrial damage. The molecular basis of the underlying pathologies included inflammation, pyroptosis, apoptosis, and necroptosis. These pathological changes are partially linked to renal diseases such as diabetic nephropathy, hypertensive nephrosclerosis, and ischemic reperfusion injury. Adem rats could help understand the common pathological mechanisms of these renal diseases and develop therapeutic strategies.

physiology↗

bioRxiv2021

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.

neuroscience↗

bioRxiv2021

CUX2 mutations in temporal lobe epilepsy; increased kainate susceptibility and excitatory input to hippocampus in deficient mice

CUX2 gene encodes a transcription factor that controls neuronal proliferation, dendrite branching and synapse formation, locating at the epilepsy-associated chromosomal region 12q24 that we previously identified by a genome-wide association study (GWAS) in Japanese population. A CUX2 recurrent de novo variant p.E590K has been described in patients with rare epileptic encephalopathies and the gene is a candidate for the locus, however the mutation may not be enough to generate the genome-wide significance in the GWAS and whether CUX2 variants appear in other types of epilepsies and physiopathological mechanisms are remained to be investigated. Here in this study, we conducted targeted sequencings of CUX2, a paralog CUX1 and its short isoform CASP harboring a unique C-terminus on 271 Japanese patients with a variety of epilepsies, and found that multiple CUX2 missense variants, other than the p.E590K, and some CASP variants including a deletion, predominantly appeared in patients with temporal lobe epilepsy (TLE). The CUX2 variants showed abnormal localization in human cell culture analysis. While wild-type CUX2 enhances dendritic arborization in fly neurons, the effect was compromised by some of the variants. Cux2- and Casp-specific knockout mice both showed high susceptibility to kainate, increased excitatory cell number in the entorhinal cortex, and significant enhancement in glutamatergic synaptic transmission to the hippocampus. CASP and CUX2 proteins physiologically bound to each other and co-expressed in excitatory neurons in brain regions including the entorhinal cortex. These results suggest that CUX2 and CASP variants contribute to the TLE pathology through a facilitation of excitatory synaptic transmission from entorhinal cortex to hippocampus.

neuroscience↗