期刊
REDOX BIOLOGY
卷 45, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.redox.2021.102057
关键词
Glyoxalase 1; Vitamin B6; Methylglyoxal; Schizophrenia; Mitochondria; Oxidative stress
资金
- JSPS Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers [S2603]
- JSPS KAKENHI [16H05380, 17H05930, 18K06977, 19H04887, 20H03608]
- AMED [JP20dm0107088]
- Kanae Foundation for the Promotion of Medical Science
- Uehara Memorial Foundation
- Sumitomo Foundation
- SENSHIN Medical Research Foundation
- Grants-in-Aid for Scientific Research [18K06977, 16H05380, 17H05930, 19H04887, 20H03608] Funding Source: KAKEN
This study identified a subtype of schizophrenia patients with novel mutations in the GLO1 gene that results in reductions of enzymatic activity and vitamin B6 deficiency. Through a mouse model, the researchers found that the combination of GLO1 dysfunction and VB6 deficiency may lead to behavioral deficits in schizophrenia patients, possibly through mitochondrial dysfunction and oxidative stress in the prefrontal cortex.
Methylglyoxal (MG) is a reactive and cytotoxic alpha-dicarbonyl byproduct of glycolysis. Our bodies have several biodefense systems to detoxify MG, including an enzymatic system by glyoxalase (GLO) 1 and GLO2. We identified a subtype of schizophrenia patients with novel mutations in the GLO1 gene that results in reductions of enzymatic activity. Moreover, we found that vitamin B6 (VB6) levels in peripheral blood of the schizophrenia patients with GLO1 dysfunction are significantly lower than that of healthy controls. However, the effects of GLO1 dysfunction and VB6 deficiency on the pathophysiology of schizophrenia remains poorly understood. Here, we generated a novel mouse model for this subgroup of schizophrenia patients by feeding Glo1 knockout mice VB6-deficent diets (KO/VB6(-)) and evaluated the combined effects of GLO1 dysfunction and VB6 deficiency on brain function. KO/VB6(-) mice accumulated homocysteine in plasma and MG in the prefrontal cortex (PFC), hippocampus, and striatum, and displayed behavioral deficits, such as impairments of social interaction and cognitive memory and a sensorimotor deficit in the prepulse inhibition test. Furthermore, we found aberrant gene expression related to mitochondria function in the PFC of the KO/VB6(-) mice by RNA-sequencing and weighted gene co-expression network analysis (WGCNA). Finally, we demonstrated abnormal mitochondrial respiratory function and subsequently enhanced oxidative stress in the PFC of KO/VB6(-) mice in the PFC. These findings suggest that the combination of GLO1 dysfunction and VB6 deficiency may cause the observed behavioral deficits via mitochondrial dysfunction and oxidative stress in the PFC.
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