TY - JOUR
T1 - Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology
AU - Ide, Masayuki
AU - Ohnishi, Tetsuo
AU - Toyoshima, Manabu
AU - Balan, Shabeesh
AU - Maekawa, Motoko
AU - Shimamoto-Mitsuyama, Chie
AU - Iwayama, Yoshimi
AU - Ohba, Hisako
AU - Watanabe, Akiko
AU - Ishii, Takashi
AU - Shibuya, Norihiro
AU - Kimura, Yuka
AU - Hisano, Yasuko
AU - Murata, Yui
AU - Hara, Tomonori
AU - Morikawa, Momo
AU - Hashimoto, Kenji
AU - Nozaki, Yayoi
AU - Toyota, Tomoko
AU - Wada, Yuina
AU - Tanaka, Yosuke
AU - Kato, Tadafumi
AU - Nishi, Akinori
AU - Fujisawa, Shigeyoshi
AU - Okano, Hideyuki
AU - Itokawa, Masanari
AU - Hirokawa, Nobutaka
AU - Kunii, Yasuto
AU - Kakita, Akiyoshi
AU - Yabe, Hirooki
AU - Iwamoto, Kazuya
AU - Meno, Kohji
AU - Katagiri, Takuya
AU - Dean, Brian
AU - Uchida, Kazuhiko
AU - Kimura, Hideo
AU - Yoshikawa, Takeo
N1 - Funding Information:
We deeply thank Yuko Fukata (National Institute for Physiological Sciences) for valuable suggestions regarding the palmitoylation assay. We are grateful to Noriyuki Nagahara (Nippon Medical School) for kindly providing the anti‐Mpst polyclonal antibody (Nagahara ). pCAGGS (Niwa ) was provided by the RIKEN BRC through the National BioResource Project of the MEXT/AMED, Japan. We also thank members of Research Resources Division, RIKEN CBS, for animal maintenance, embryo manipulation, metabolite analysis and DNA sequencing service, Takashi Asada for his help for the establishment of collaborative team, Miyuki Kato and Santha Kumara Dissanayaka for technical assistance, Atsuko Nagata, Junya Matsumoto and Mizuki Hino for the preparation of postmortem brain samples, Tomoe Ichikawa, Kazuya Toriumi and Akiko Kobori for their help for collecting scalp hair follicle samples, Masaomi Iyo and Toshihisa Niitsu for collecting plasma samples, Tadayuki Ogawa for his help for spine analysis, and Makoto Asashima and Renpei Nagashima for their helpful comments and discussions. This study was supported by the Strategic Research Program for Brain Sciences from Japan Agency for Medical Research and Development (AMED) under Grant Numbers JP18dm0107083 (TY), JP19dm0107083 (TY), JP18dm0107085 (HK), JP19dm0107119 (KH), JP19dm0908001 (NH), 19dm0107086 (YKu), and 19dm0107107 (HY), and by the Grant‐in‐Aid for Scientific Research on Innovative Areas from the MEXT under Grant Numbers JP18H05435 (TY), JP18H05428 (TY), and JP16H06277 (HY), and by JSPS KAKENHI under Grant Number JP17H01574 (TY). This study was also supported in part by Grants‐in‐Aid for NEDO (New Energy and Industrial Technology Development Organization) (KU). This work was performed in part as a collaborative research effort of Clinical Bioinformatics Research Initiative (CBIRI) at the National Institute of Advanced Industrial Science and Technology (AIST), Japan. et al , et al ,
Funding Information:
We deeply thank Yuko Fukata (National Institute for Physiological Sciences) for valuable suggestions regarding the palmitoylation assay. We are grateful to Noriyuki Nagahara (Nippon Medical School) for kindly providing the anti-Mpst polyclonal antibody (Nagahara et?al,). pCAGGS (Niwa et?al,) was provided by the RIKEN BRC through the National BioResource Project of the MEXT/AMED, Japan. We also thank members of Research Resources Division, RIKEN CBS, for animal maintenance, embryo manipulation, metabolite analysis and DNA sequencing service, Takashi Asada for his help for the establishment of collaborative team, Miyuki Kato and Santha Kumara Dissanayaka for technical assistance, Atsuko Nagata, Junya Matsumoto and Mizuki Hino for the preparation of postmortem brain samples, Tomoe Ichikawa, Kazuya Toriumi and Akiko Kobori for their help for collecting scalp hair follicle samples, Masaomi Iyo and Toshihisa Niitsu for collecting plasma samples, Tadayuki Ogawa for his help for spine analysis, and Makoto Asashima and Renpei Nagashima for their helpful comments and discussions. This study was supported by the Strategic Research Program for Brain Sciences from Japan Agency for Medical Research and Development (AMED) under Grant Numbers JP18dm0107083 (TY), JP19dm0107083 (TY), JP18dm0107085 (HK), JP19dm0107119 (KH), JP19dm0908001 (NH), 19dm0107086 (YKu), and 19dm0107107 (HY), and by the Grant-in-Aid for Scientific Research on Innovative Areas from the MEXT under Grant Numbers JP18H05435 (TY), JP18H05428 (TY), and JP16H06277 (HY), and by JSPS KAKENHI under Grant Number JP17H01574 (TY). This study was also supported in part by Grants-in-Aid for NEDO (New Energy and Industrial Technology Development Organization) (KU). This work was performed in part as a collaborative research effort of Clinical Bioinformatics Research Initiative (CBIRI) at the National Institute of Advanced Industrial Science and Technology (AIST), Japan.
Publisher Copyright:
© 2019 The Authors. Published under the terms of the CC BY 4.0 license
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
KW - energy metabolism
KW - epigenetics
KW - hydrogen sulfide and polysulfides
KW - prepulse inhibition
KW - proteomics
UR - http://www.scopus.com/inward/record.url?scp=85074585841&partnerID=8YFLogxK
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U2 - 10.15252/emmm.201910695
DO - 10.15252/emmm.201910695
M3 - Article
C2 - 31657521
AN - SCOPUS:85074585841
SN - 1757-4676
VL - 11
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 12
M1 - e10695
ER -