論文

国際誌
2021年9月

Combined glyoxalase 1 dysfunction and vitamin B6 deficiency in a schizophrenia model system causes mitochondrial dysfunction in the prefrontal cortex.

Redox biology
  • Kazuya Toriumi
  • ,
  • Stefano Berto
  • ,
  • Shin Koike
  • ,
  • Noriyoshi Usui
  • ,
  • Takashi Dan
  • ,
  • Kazuhiro Suzuki
  • ,
  • Mitsuhiro Miyashita
  • ,
  • Yasue Horiuchi
  • ,
  • Akane Yoshikawa
  • ,
  • Mai Asakura
  • ,
  • Kenichiro Nagahama
  • ,
  • Hsiao-Chun Lin
  • ,
  • Yuki Sugaya
  • ,
  • Takaki Watanabe
  • ,
  • Masanobu Kano
  • ,
  • Yuki Ogasawara
  • ,
  • Toshio Miyata
  • ,
  • Masanari Itokawa
  • ,
  • Genevieve Konopka
  • ,
  • Makoto Arai

45
開始ページ
102057
終了ページ
102057
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1016/j.redox.2021.102057

Methylglyoxal (MG) is a reactive and cytotoxic α-dicarbonyl byproduct of glycolysis. Our bodies have several bio-defense 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.

リンク情報
DOI
https://doi.org/10.1016/j.redox.2021.102057
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/34198071
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253914
ID情報
  • DOI : 10.1016/j.redox.2021.102057
  • PubMed ID : 34198071
  • PubMed Central 記事ID : PMC8253914

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