Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology.,EMBO Molecular Medicine

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Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology.
EMBO Molecular Medicine ( IF 9.0 ) Pub Date : 2019-10-28 , DOI: 10.15252/emmm.201910695
Masayuki Ide _{1,

2} , Tetsuo Ohnishi ₁ , Manabu Toyoshima ₁ , Shabeesh Balan ₁ , Motoko Maekawa ₁ , Chie Shimamoto-Mitsuyama ₁ , Yoshimi Iwayama _{1,

3} , Hisako Ohba ₁ , Akiko Watanabe ₁ , Takashi Ishii ₄ , Norihiro Shibuya _{5,

6} , Yuka Kimura _{5,

6} , Yasuko Hisano ₁ , Yui Murata ₇ , Tomonori Hara _{1,

8} , Momo Morikawa ₉ , Kenji Hashimoto ₁₀ , Yayoi Nozaki ₁ , Tomoko Toyota ₁ , Yuina Wada _{1,

11} , Yosuke Tanaka ₉ , Tadafumi Kato ₁₂ , Akinori Nishi ₁₃ , Shigeyoshi Fujisawa ₁₄ , Hideyuki Okano ₁₅ , Masanari Itokawa ₁₆ , Nobutaka Hirokawa ₉ , Yasuto Kunii _{17,

18} , Akiyoshi Kakita ₁₉ , Hirooki Yabe ₁₇ , Kazuya Iwamoto ₇ , Kohji Meno ₄ , Takuya Katagiri ₂₀ , Brian Dean _{21,

22} , Kazuhiko Uchida ₂₃ , Hideo Kimura _{5,

6} , Takeo Yoshikawa ₁

Affiliation

Laboratory of Molecular Psychiatry, RIKEN Center for Brain Science, Wako, Saitama, Japan.
Department of Psychiatry, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Support Unit for Bio-Material Analysis, Research Division, RIKEN Center for Brain Science, Wako, Saitama, Japan.
Research& Development Department, MCBI Inc, Tsukuba, Ibaraki, Japan.
Department of Pharmacology, Sanyo-Onoda City University, Sanyo-Onoda, Yamaguchi, Japan.
Department of Molecular Pharmacology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
Department of Molecular Brain Science, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Department of Organ Anatomy, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
Graduate School of Humanities and Sciences, Ochanomizu University, Tokyo, Japan.
Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Center for Brain Science, Wako, Saitama, Japan.
Department of Pharmacology, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
Laboratory for Systems Neurophysiology, RIKEN Center for Brain Science, Wako, Saitama, Japan.
Department of Physiology, Keio University School of Medicine, Tokyo, Japan.
Center for Medical Cooperation, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Department of Neuropsychiatry, School of Medicine, Fukushima Medical University, Fukushima, Japan.
Department of Psychiatry, Aizu Medical Center, Fukushima Medical University, Aizuwakamatsu, Fukushima, Japan.
Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan.
Department of Pharmacy, Faculty of Pharmacy, Iryo Sosei University, Iwaki, Fukushima, Japan.
The Florey Institute of Neuroscience and Mental Health, Howard Florey Laboratories, The University of Melbourne, Parkville, Vic., Australia.
The Centre for Mental Health, Swinburne University, Hawthorn, Vic., Australia.
Department of Molecular Oncology, Division of Biomedical Science, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.

Mice with the C3H background show greater behavioral propensity for schizophrenia, including lower prepulse inhibition (PPI), than C57BL/6 (B6) mice. To characterize as-yet-unknown pathophysiologies of schizophrenia, we undertook proteomics analysis of the brain in these strains, and detected elevated levels of Mpst, a hydrogen sulfide (H2 S)/polysulfide-producing enzyme, and greater sulfide deposition in C3H than B6 mice. Mpst-deficient mice exhibited improved PPI with reduced storage sulfide levels, while Mpst-transgenic (Tg) mice showed deteriorated PPI, suggesting that "sulfide stress" may be linked to PPI impairment. Analysis of human samples demonstrated that the H2 S/polysulfides production system is upregulated in schizophrenia. Mechanistically, the Mpst-Tg brain revealed dampened energy metabolism, while maternal immune activation model mice showed upregulation of genes for H2 S/polysulfides production along with typical antioxidative genes, partly via epigenetic modifications. These results suggest that inflammatory/oxidative insults in early brain development result in upregulated H2 S/polysulfides production as an antioxidative response, which in turn cause deficits in bioenergetic processes. Collectively, this study presents a novel aspect of the neurodevelopmental theory for schizophrenia, unraveling a role of excess H2 S/polysulfides production.

中文翻译：

过量的硫化氢和多硫化物的产生是精神分裂症病理生理学的基础。

与C57BL / 6（B6）小鼠相比，具有C3H背景的小鼠对精神分裂症表现出更大的行为倾向，包括较低的脉冲前抑制（PPI）。为了表征精神分裂症的迄今未知的病理生理学，我们对这些菌株的大脑进行了蛋白质组学分析，并检测到Mpst水平升高，硫化氢（H2 S）/多硫化物生成酶水平升高，并且C3H中的硫化物沉积量高于B6老鼠。缺乏Mpst的小鼠表现出改善的PPI，降低了储存的硫化物水平，而具有Mpst的转基因（Tg）小鼠表现出恶化的PPI，表明“硫化物应激”可能与PPI损伤有关。对人体样品的分析表明，精神分裂症中的H2 S /多硫化物生产系统上调。从机制上讲，Mpst-Tg脑显示能量代谢受阻，而母体免疫激活模型小鼠则部分通过表观遗传修饰，显示出H2 S /多硫化物生成基因以及典型的抗氧化基因上调。这些结果表明，早期大脑发育中的炎症/氧化性损伤导致H2 S /多硫化物的产生上调，这是一种抗氧化反应，进而导致生物能过程不足。总的来说，这项研究提出了精神分裂症神经发育理论的一个新方面，揭示了过量H2 S /多硫化物产生的作用。这些结果表明，早期大脑发育中的炎症/氧化性损伤导致H2 S /多硫化物的产生上调，这是一种抗氧化反应，进而导致生物能过程不足。总的来说，这项研究提出了精神分裂症神经发育理论的一个新方面，揭示了过量H2 S /多硫化物产生的作用。这些结果表明，早期大脑发育中的炎症/氧化性损伤导致H2 S /多硫化物的产生上调，这是一种抗氧化反应，进而导致生物能过程不足。总的来说，这项研究提出了精神分裂症神经发育理论的一个新方面，揭示了过量H2 S /多硫化物产生的作用。

更新日期：2019-12-06

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