Impairment of methylglyoxal detoxification systems causes mitochondrial dysfunction and schizophrenia-like behavioral deficits

Toriumi, Kazuya; Berto, Stefano; Koike, Sachiko; Usui, Noriyoshi; Dan, Takashi; Suzuki, Kazuhiro; Miyashita, Mitsuhiro; Horiuchi, Yasue; Yoshikawa, Akane; Sugaya, Yuki; Watanabe, Takaki; Asakura, Mai; Kano, Masanobu; Ogasawara, Yuki; Miyata, Toshio; Itokawa, Masanari; Konopka, Genevieve; Arai, Makoto

doi:10.1101/2020.07.08.192906

Cited by 2 publications

(2 citation statements)

References 72 publications

(66 reference statements)

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“…Eight-week-old Glo1 -KO mice were fed a VB6-deficit diet for 4 weeks and referred to as “CS-SCZ model mice.” In addition, 8-week-old Glo1 -KO mice fed with a normal diet for 4 weeks, and 8-week-old C57BL/6J wild-type (WT) mice fed with a normal diet or VB6-deficit diet for 4 weeks were used as three control groups [ 18 ].…”

Section: Methodsmentioning

confidence: 99%

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Accumulation of Carbonyl Proteins in the Brain of Mouse Model for Methylglyoxal Detoxification Deficits

et al. 2021

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Recent studies have shown that carbonyl stress is a causative factor of schizophrenia, categorized as carbonyl stress-related schizophrenia (CS-SCZ). However, the correlation between carbonyl stress and the pathogenesis of this disease is not well established. In this study, glyoxalase 1(Glo1)-knockout and vitamin B6-deficient mice (KO/VB6 (-) mice), which are susceptible to methylglyoxal (MGO)-induced oxidative damages, were used as a CS-SCZ model to analyze MGO-modified protein and the carbonyl stress status in the brain. A comparison between Wild/VB6(+) mice and KO/VB6(−) mice for accumulated carbonyl proteins levels, with several advanced glycation end products (AGEs) in the brain, revealed that carbonyl protein levels with the Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl) ornithine (MG-H1) moiety were significantly increased in the hippocampus, prefrontal cortex, striatum, cerebral cortex, and brainstem regions of the brain in KO/VB6(−) mice. Moreover, two-dimensional electrophoresis and Liquid chromatography-tandem mass spectrometry analysis showed MG-H1-modified arginine residues in mitochondrial creatine kinase, beta-adrenergic receptor kinase 1, and T-complex protein in the hippocampus region of KO/VB6(−) mice, but not in Wild/VB6(+) mice. In particular, MG-H1 modification of mitochondrial creatine kinase was quite notable. These results suggest that further studies focusing on MG-H1-modified and accumulated proteins in the hippocampus may reveal the onset mechanism of CS-SCZ induced by MGO-induced oxidative damages.

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Section: Methodsmentioning

confidence: 99%

“…KO, HE, and wild-type mice (WT) were identified by PCR genotyping before being subjected to further studies. No significant increases in the gene expression of Akr family and Park7 were confirmed in Glo1-KO mice [ 18 ].…”

Section: Methodsmentioning

confidence: 99%

Accumulation of Carbonyl Proteins in the Brain of Mouse Model for Methylglyoxal Detoxification Deficits

et al. 2021

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High Sucrose Diets Contribute to Brain Angiopathy with Impaired Glucose Uptake, and Psychosis-related Higher Brain Dysfunctions in Mice

Hirai

Miwa

Tanaka

et al. 2020

Preprint

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Psychiatric disorders are associated with metabolic dysfunction, but it is unclear whether our current high-sugar diet contributes to pathogenesis. We demonstrate that a high-sucrose diet during adolescence induces behavioral phenotypes of psychiatric disease, such as hyperactivity, poor working memory, anxiety, and impaired sensory gating, in mice deficient for glyoxalase-1, an enzyme involved in detoxification of sucrose metabolites. The high-sucrose diet also induced advanced glycation end product accumulation in brain microcapillary endothelium, disrupted interneuron function and striatal dopamine release, and reduced brain glucose uptake. Aspirin protected against this angiopathy, enhanced brain glucose uptake, and prevented abnormal behavioral phenotypes. Brains from schizophrenia and bipolar disorder patients exhibited similar angiopathy. Psychiatric disorders are associated with microvascular brain damage, possibly due to variety of environmental stresses including metabolic stress.One Sentence SummaryWe demonstrate neural angiopathy and multiple endophenotypes of psychiatric disease in a mouse model of impaired glucose metabolism due to excessive sugar intake and confirm neural angiopathy in postmortem brains of schizophrenia and bipolar disorder patients.

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Impairment of methylglyoxal detoxification systems causes mitochondrial dysfunction and schizophrenia-like behavioral deficits

Cited by 2 publications

References 72 publications

Accumulation of Carbonyl Proteins in the Brain of Mouse Model for Methylglyoxal Detoxification Deficits

Accumulation of Carbonyl Proteins in the Brain of Mouse Model for Methylglyoxal Detoxification Deficits

High Sucrose Diets Contribute to Brain Angiopathy with Impaired Glucose Uptake, and Psychosis-related Higher Brain Dysfunctions in Mice

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