Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology
Abstract 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 detect...
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Springer Nature
2019-10-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201910695 |
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| author | Masayuki Ide Tetsuo Ohnishi Manabu Toyoshima Shabeesh Balan Motoko Maekawa Chie Shimamoto‐Mitsuyama Yoshimi Iwayama Hisako Ohba Akiko Watanabe Takashi Ishii Norihiro Shibuya Yuka Kimura Yasuko Hisano Yui Murata Tomonori Hara Momo Morikawa Kenji Hashimoto Yayoi Nozaki Tomoko Toyota Yuina Wada Yosuke Tanaka Tadafumi Kato Akinori Nishi Shigeyoshi Fujisawa Hideyuki Okano Masanari Itokawa Nobutaka Hirokawa Yasuto Kunii Akiyoshi Kakita Hirooki Yabe Kazuya Iwamoto Kohji Meno Takuya Katagiri Brian Dean Kazuhiko Uchida Hideo Kimura Takeo Yoshikawa |
| author_facet | Masayuki Ide Tetsuo Ohnishi Manabu Toyoshima Shabeesh Balan Motoko Maekawa Chie Shimamoto‐Mitsuyama Yoshimi Iwayama Hisako Ohba Akiko Watanabe Takashi Ishii Norihiro Shibuya Yuka Kimura Yasuko Hisano Yui Murata Tomonori Hara Momo Morikawa Kenji Hashimoto Yayoi Nozaki Tomoko Toyota Yuina Wada Yosuke Tanaka Tadafumi Kato Akinori Nishi Shigeyoshi Fujisawa Hideyuki Okano Masanari Itokawa Nobutaka Hirokawa Yasuto Kunii Akiyoshi Kakita Hirooki Yabe Kazuya Iwamoto Kohji Meno Takuya Katagiri Brian Dean Kazuhiko Uchida Hideo Kimura Takeo Yoshikawa |
| author_sort | Masayuki Ide |
| collection | DOAJ |
| description | Abstract 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 (H2S)/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 H2S/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 H2S/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 H2S/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 H2S/polysulfides production. |
| format | Article |
| id | doaj-art-7d421ed9c97e4545be1c2101a84acaa4 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2019-10-01 |
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| series | EMBO Molecular Medicine |
| spelling | doaj-art-7d421ed9c97e4545be1c2101a84acaa42025-08-20T03:43:10ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842019-10-01111212410.15252/emmm.201910695Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiologyMasayuki Ide0Tetsuo Ohnishi1Manabu Toyoshima2Shabeesh Balan3Motoko Maekawa4Chie Shimamoto‐Mitsuyama5Yoshimi Iwayama6Hisako Ohba7Akiko Watanabe8Takashi Ishii9Norihiro Shibuya10Yuka Kimura11Yasuko Hisano12Yui Murata13Tomonori Hara14Momo Morikawa15Kenji Hashimoto16Yayoi Nozaki17Tomoko Toyota18Yuina Wada19Yosuke Tanaka20Tadafumi Kato21Akinori Nishi22Shigeyoshi Fujisawa23Hideyuki Okano24Masanari Itokawa25Nobutaka Hirokawa26Yasuto Kunii27Akiyoshi Kakita28Hirooki Yabe29Kazuya Iwamoto30Kohji Meno31Takuya Katagiri32Brian Dean33Kazuhiko Uchida34Hideo Kimura35Takeo Yoshikawa36Laboratory of Molecular Psychiatry, RIKEN Center for Brain ScienceLaboratory of Molecular Psychiatry, RIKEN Center for Brain ScienceLaboratory of Molecular Psychiatry, RIKEN Center for Brain ScienceLaboratory of Molecular Psychiatry, RIKEN Center for Brain ScienceLaboratory of Molecular Psychiatry, RIKEN Center for Brain ScienceLaboratory of Molecular Psychiatry, RIKEN Center for Brain ScienceLaboratory of Molecular Psychiatry, RIKEN Center for Brain ScienceLaboratory of Molecular Psychiatry, RIKEN Center for Brain ScienceLaboratory of Molecular Psychiatry, RIKEN Center for Brain ScienceResearch& Development Department, MCBI IncDepartment of Pharmacology, Sanyo‐Onoda City UniversityDepartment of Pharmacology, Sanyo‐Onoda City UniversityLaboratory of Molecular Psychiatry, RIKEN Center for Brain ScienceDepartment of Molecular Brain Science, Graduate School of Medical Sciences, Kumamoto UniversityLaboratory of Molecular Psychiatry, RIKEN Center for Brain ScienceDepartment of Cell Biology and Anatomy, Graduate School of Medicine, The University of TokyoDivision of Clinical Neuroscience, Chiba University Center for Forensic Mental HealthLaboratory of Molecular Psychiatry, RIKEN Center for Brain ScienceLaboratory of Molecular Psychiatry, RIKEN Center for Brain ScienceLaboratory of Molecular Psychiatry, RIKEN Center for Brain ScienceDepartment of Cell Biology and Anatomy, Graduate School of Medicine, The University of TokyoLaboratory for Molecular Dynamics of Mental Disorders, RIKEN Center for Brain ScienceDepartment of Pharmacology, Kurume University School of MedicineLaboratory for Systems Neurophysiology, RIKEN Center for Brain ScienceDepartment of Physiology, Keio University School of MedicineCenter for Medical Cooperation, Tokyo Metropolitan Institute of Medical ScienceDepartment of Cell Biology and Anatomy, Graduate School of Medicine, The University of TokyoDepartment of Neuropsychiatry, School of Medicine, Fukushima Medical UniversityDepartment of Pathology, Brain Research Institute, Niigata UniversityDepartment of Neuropsychiatry, School of Medicine, Fukushima Medical UniversityDepartment of Molecular Brain Science, Graduate School of Medical Sciences, Kumamoto UniversityResearch& Development Department, MCBI IncDepartment of Pharmacy, Faculty of Pharmacy, Iryo Sosei UniversityThe Florey Institute of Neuroscience and Mental Health, Howard Florey Laboratories, The University of MelbourneDepartment of Molecular Oncology, Division of Biomedical Science, Faculty of Medicine, University of TsukubaDepartment of Pharmacology, Sanyo‐Onoda City UniversityLaboratory of Molecular Psychiatry, RIKEN Center for Brain ScienceAbstract 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 (H2S)/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 H2S/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 H2S/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 H2S/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 H2S/polysulfides production.https://doi.org/10.15252/emmm.201910695energy metabolismepigeneticshydrogen sulfide and polysulfidesprepulse inhibitionproteomics |
| spellingShingle | Masayuki Ide Tetsuo Ohnishi Manabu Toyoshima Shabeesh Balan Motoko Maekawa Chie Shimamoto‐Mitsuyama Yoshimi Iwayama Hisako Ohba Akiko Watanabe Takashi Ishii Norihiro Shibuya Yuka Kimura Yasuko Hisano Yui Murata Tomonori Hara Momo Morikawa Kenji Hashimoto Yayoi Nozaki Tomoko Toyota Yuina Wada Yosuke Tanaka Tadafumi Kato Akinori Nishi Shigeyoshi Fujisawa Hideyuki Okano Masanari Itokawa Nobutaka Hirokawa Yasuto Kunii Akiyoshi Kakita Hirooki Yabe Kazuya Iwamoto Kohji Meno Takuya Katagiri Brian Dean Kazuhiko Uchida Hideo Kimura Takeo Yoshikawa Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology EMBO Molecular Medicine energy metabolism epigenetics hydrogen sulfide and polysulfides prepulse inhibition proteomics |
| title | Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology |
| title_full | Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology |
| title_fullStr | Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology |
| title_full_unstemmed | Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology |
| title_short | Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology |
| title_sort | excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology |
| topic | energy metabolism epigenetics hydrogen sulfide and polysulfides prepulse inhibition proteomics |
| url | https://doi.org/10.15252/emmm.201910695 |
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