Journal article
Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology
M Ide, T Ohnishi, M Toyoshima, S Balan, M Maekawa, C Shimamoto-Mitsuyama, Y Iwayama, H Ohba, A Watanabe, T Ishii, N Shibuya, Y Kimura, Y Hisano, Y Murata, T Hara, M Morikawa, K Hashimoto, Y Nozaki, T Toyota, Y Wada Show all
EMBO Molecular Medicine | WILEY | Published : 2019
Open access
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 produc..
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Awarded by New Energy and Industrial Technology Development Organization
Funding Acknowledgements
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, 1998). pCAGGS (Niwa et al, 1991) 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.