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

Shin Koike,Yosuke Kibune,Kazuya Toriumi,Takashi Dan,Yuki Ogasawara,Sakura Kasahara,Toshio Miyata,Yo-Ichi Ishida,Makoto Arai

doi:10.3390/antiox10040574

Abstract

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.

Highlights

Schizophrenia (SCZ) causes severe mental disability and affects approximately 1% of the global population [1]
The accumulation of carbonyl proteins was detected in six different regions of the mouse brain using Western blot analysis
The present study evaluated the state of carbonyl stress in KO/VB6(−) mice as a carbonyl stress-related schizophrenia (CS-SCZ) model by examining the changes in carbonyl protein with advanced glycation end products (AGEs) in the brain, in order to investigate the mechanism of SCZ pathogenesis

Summary

Introduction

Schizophrenia (SCZ) causes severe mental disability and affects approximately 1% of the global population [1]. Several studies have been conducted to understand the underlying mechanism of the disease, the main cause and pathophysiology of SCZ remains elusive, in part due to considerable heterogeneity in its symptoms and the long-term clinical courses between patients. To understand the onset mechanism, we focused on the involvement of carbonyl stress-related schizophrenia (CS-SCZ), which was recently discovered in a population of patients with refractory SCZ [2,3,4,5,6]. Antioxidants 2021, 10, 574 the formation of advanced glycation end products (AGEs) through a complex mechanism. We previously reported that a significant number of patients (approximately 20%) with SCZ showed high levels of blood pentosidine (PEN), a typical AGE, or low levels of vitamin

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Conclusion