@article{e90c5e3fe93344d5b838f6bdc6327618,
title = "Betaine ameliorates schizophrenic traits by functionally compensating for KIF3-based CRMP2 transport",
abstract = "In schizophrenia (SCZ), neurons in the brain tend to undergo gross morphological changes, but the related molecular mechanism remains largely elusive. Using Kif3b+/− mice as a model with SCZ-like behaviors, we found that a high-betaine diet can significantly alleviate schizophrenic traits related to neuronal morphogenesis and behaviors. According to a deficiency in the transport of collapsin response mediator protein 2 (CRMP2) by the KIF3 motor, we identified a significant reduction in lamellipodial dynamics in developing Kif3b+/− neurons as a cause of neurite hyperbranching. Betaine administration significantly decreases CRMP2 carbonylation, which enhances the F-actin bundling needed for proper lamellipodial dynamics and microtubule exclusion and may thus functionally compensate for KIF3 deficiency. Because the KIF3 expression levels tend to be downregulated in the human prefrontal cortex of the postmortem brains of SCZ patients, this mechanism may partly participate in human SCZ pathogenesis, which we hypothesize could be alleviated by betaine administration.",
keywords = "actin dynamics, betaine, carbonylation, CRMP2, KIF3, kinesin, lamellipodia, neurite branching, schizophrenia, social interaction",
author = "Shogo Yoshihara and Xuguang Jiang and Momo Morikawa and Tadayuki Ogawa and Sotaro Ichinose and Hirooki Yabe and Akiyoshi Kakita and Manabu Toyoshima and Yasuto Kunii and Takeo Yoshikawa and Yosuke Tanaka and Nobutaka Hirokawa",
note = "Funding Information: We thank previous and current members of the N.H., T.Y., and Y.K. laboratories for valuable suggestions and help, especially Sen Takeda (Yamanashi University) and Yasuko Noda (Jichi Medical University) for an initial analysis of CRMP2, Manatsu Morikawa; Haruyo Fukuda, Hiromi Sato, Nobuhisa Onouchi, and Tsuyoshi Akamatsu (The University of Tokyo) for technical assistance; Mizuki Hino (Fukushima Medical University) for technical help with the ELISAs; and Hisako Ohba and Akiko Watanabe (RIKEN) for technical help with the mouse behavioral tests. We also thank Takehide Oda (ZEISS) for the SEM analyses; Rie Hayashi (ZEISS) for the help with four-color immunofluorescence microscopy; Satoru Kondo, Masumi Asahara (ICRN, The University of Tokyo), and Suguru Osari (Leica Japan) for help with STED microscopy; Hideaki Iigusa (Keyence) for help with light microscopy; Hiroko Kitagawa (Jasco) for help with the actin polymerization assay; Kyohhei Fujita (The University of Tokyo) for help with the structural formula of betaine; Michael Sixt and Roland Wedlich-Soldner (Max Planck Institute for Biochemistry, Germany) for providing the Lifeact-mRuby mice; and Yoshiaki Hagiwara and Kazutaka Matsunami (Immuno-Biological Laboratories) for help with the direct ELISAs. This study was supported by the Strategic Research Program for Brain Sciences from AMED (grant nos. JP20dm0107084 to N.H. and Y.T.; JP20dm0107083 to T.Y.; JP19dm0107086 and 19dm0207074 to Y.K.; JP19dm0107107 to H.Y.; and JP19dm0107104 to A.K.); the Grant-in-Aid for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Sports, Science and Technology of Japan (grant nos. JP16H06277 to H.Y. and JP19H05223 to Y.K.); the Collaborative Research Project of the Brain Research Institute, Niigata University (grant no. 201917 to Y.K.); and by the World-leading Innovative Graduate Study Program for Life Science and Technology, The University of Tokyo , as part of the WISE Program (Doctoral Program for World-leading Innovative & Smart Education), MEXT, Japan (to S.Y.). This work was supported also by the Japan Electron Optics Laboratory (JEOL) to N.H. Funding Information: We thank previous and current members of the N.H. T.Y. and Y.K. laboratories for valuable suggestions and help, especially Sen Takeda (Yamanashi University) and Yasuko Noda (Jichi Medical University) for an initial analysis of CRMP2, Manatsu Morikawa; Haruyo Fukuda, Hiromi Sato, Nobuhisa Onouchi, and Tsuyoshi Akamatsu (The University of Tokyo) for technical assistance; Mizuki Hino (Fukushima Medical University) for technical help with the ELISAs; and Hisako Ohba and Akiko Watanabe (RIKEN) for technical help with the mouse behavioral tests. We also thank Takehide Oda (ZEISS) for the SEM analyses; Rie Hayashi (ZEISS) for the help with four-color immunofluorescence microscopy; Satoru Kondo, Masumi Asahara (ICRN, The University of Tokyo), and Suguru Osari (Leica Japan) for help with STED microscopy; Hideaki Iigusa (Keyence) for help with light microscopy; Hiroko Kitagawa (Jasco) for help with the actin polymerization assay; Kyohhei Fujita (The University of Tokyo) for help with the structural formula of betaine; Michael Sixt and Roland Wedlich-Soldner (Max Planck Institute for Biochemistry, Germany) for providing the Lifeact-mRuby mice; and Yoshiaki Hagiwara and Kazutaka Matsunami (Immuno-Biological Laboratories) for help with the direct ELISAs. This study was supported by the Strategic Research Program for Brain Sciences from AMED (grant nos. JP20dm0107084 to N.H. and Y.T.; JP20dm0107083 to T.Y.; JP19dm0107086 and 19dm0207074 to Y.K.; JP19dm0107107 to H.Y.; and JP19dm0107104 to A.K.); the Grant-in-Aid for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Sports, Science and Technology of Japan (grant nos. JP16H06277 to H.Y. and JP19H05223 to Y.K.); the Collaborative Research Project of the Brain Research Institute, Niigata University (grant no. 201917 to Y.K.); and by the World-leading Innovative Graduate Study Program for Life Science and Technology, The University of Tokyo, as part of the WISE Program (Doctoral Program for World-leading Innovative & Smart Education), MEXT, Japan (to S.Y.). This work was supported also by the Japan Electron Optics Laboratory (JEOL) to N.H. N.H. conceived and directed the project. S.Y. Y.T. and N.H. designed the experiments. S.Y. performed most of the experiments and statistical analyses with support from S.I. Y.T. T.O. X.J. and M.M. Y.T. and S.Y. performed the STED microscopy. M.M. performed the PPI test. T.O. and X.J. contributed to the biochemistry experiments. M.T. and T.Y. contributed to the iPSC experiment. H.Y. A.K. and Y.K. contributed to the human postmortem brain experiment. S.Y. Y.T. T.O. and N.H. wrote the manuscript. All of the authors discussed the data and reviewed the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = apr,
day = "13",
doi = "10.1016/j.celrep.2021.108971",
language = "English",
volume = "35",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "2",
}