Novel approaches to drug development of schizophrenia

• Project/Area Number: 18K07578
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52030:Psychiatry-related
• Research Institution: Tohoku University (2022); Institute of Physical and Chemical Research (2018-2020)
• Principal Investigator: Maekawa Motoko 東北大学, 医学系研究科, 准教授 (50435731)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 統合失調症 / 治療 / PPARalpha / シナプス / 行動 / 遺伝子変異 / 栄養 / 脂質代謝 / fenofibrate / PPARAアゴニスト / シナプス関連遺伝子 / 治療薬 / 脳移行性 / 1細胞 / シングル核 / 遺伝子発現解析 / オリゴデンドロサイト / GABAニューロン / 核内受容体 / シングルセル / RNA-seq / 化合物ライブラリー

Outline of Final Research Achievements

We generated a model mouse that mimics the nutritional deficiency during brain development and showed that the mice exhibit schizophrenia-like phenotypes. We also revealed that dysfunction of the nuclear receptor PPARA, which uses fatty acids as endogenous ligands, may cause the risk of the phenotypes in this animal (Maekawa et al., 2017). Furthermore, we identified four variants of the PPARA gene are associated with functional changes in patients with schizophrenia. Additionally, we reported that Ppara knockout mice show schizophrenia-like behavioral changes and exhibit synaptic morphology changes similar to those observed in postmortem brains of individuals with schizophrenia. In addition, we found that PPARA agonists improved the phenotype of a drug-induced model mouse of schizophrenia (Wada, Maekawa et al., 2020). These results indicate that PPARa dysfunction is involved in the pathophysiology of schizophrenia and it shows that PPARa is a new therapeutic target for schizophrenia.

Academic Significance and Societal Importance of the Research Achievements

本研究を通じて、これまで主に脂質代謝との関連について研究されてきた核内受容体PPARAという分子が、意外にも統合失調症病態メカニズム形成に関わることを示した。また、統合失調症治療薬として、今回新たにPPARAアゴニストが候補になりうるという新しい道筋を示した。PPARAのアゴニストは、脂質代謝治療薬として臨床で広く使用されていることから、より臨床応用に近い治療標的を提示した点が本研究の特徴であると言える。一方で、PPARAのアゴニストの詳しい作用メカニズムは不明なため、今後さらに解析が必要であると考えている。

Research Products

• [Journal Article] Cooperation of LIM domain-binding 2 (LDB2) with EGR in the pathogenesis of schizophrenia. (2021)
  • Author(s): Ohnishi T, Kiyama Y, Arima-Yoshida F, Kadota M, Ichikawa T, Yamada K, Watanabe A, Ohba H, Tanaka K, Nakaya A, Horiuchi Y, Iwayama Y, Toyoshima M, Ogawa I, Shimamoto-Mitsuyama C, Maekawa M, Balan S, Arai M, Miyashita M, Toriumi K, et al.
  • Journal Title: EMBO Mol Med Volume: 13 Issue: 4
  • DOI: 10.15252/emmm.202012574
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Role of an Atypical Cadherin Gene, Cdh23 in Prepulse Inhibition and Implication of CDH23 in Schizophrenia (2021)
  • Author(s): Balan S, Ohnishi T, Watanabe A, Ohba H, Iwayama Y, Toyoshima M, Hara T, Hisano Y, Miyasaka Y, Toyota T, Shimamoto-Mitsuyama C, Maekawa M, Numata S, Ohmori T, Shimogori T, Kikkawa Y, Hayashi T, Yoshikawa T
  • Journal Title: Schizophr Bull Volume: - Issue: 4 Pages: 1190-1200
  • DOI: 10.1093/schbul/sbab007
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Peroxisome proliferator-activated receptor α as a novel therapeutic target for schizophrenia (2020)
  • Author(s): Wada, Maekawa, Ohnishi et al.
  • Journal Title: EBioMedicine Volume: 62 Pages: 103130-103130
  • DOI: 10.1016/j.ebiom.2020.103130
  • Peer Reviewed / Open Access
• [Journal Article] A potential role of fatty acid binding protein 4 in the pathophysiology of autism spectrum disorder. (2020)
  • Author(s): Maekawa M, Ohnishi T, Toyoshima M, Shimamoto-Mitsuyama C, Hamazaki K, Balan S, Wada Y, Esaki K, Takagai S, Tsuchiya KJ, Nakamura K, Iwata Y, Nara T, Iwayama Y, Toyota T, Nozaki Y, Ohba H, Watanabe A, Hisano Y, Matsuoka S, Tsujii M, Mori N, Matsuzaki H, Yoshikawa T.
  • Journal Title: Brain Communication Volume: 2(2) Issue: 2
  • DOI: 10.1093/braincomms/fcaa145
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] VLDL-specific increases of fatty acids in autism spectrum disorder correlate with social interaction. (2020)
  • Author(s): Usui N, Toyoshima M et al.
  • Journal Title: EBioMedicine Volume: 58 Pages: 102917-102917
  • DOI: 10.1016/j.ebiom.2020.102917
  • Peer Reviewed / Open Access
• [Journal Article] Lipid pathology of the corpus callosum in schizophrenia and the potential role of abnormal gene regulatory networks with reduced microglial marker expression (2020)
  • Author(s): Shimamoto-Mitsuyama Chie、Nakaya Akihiro、Esaki Kayoko、Balan Shabeesh、Iwayama Yoshimi、Ohnishi Tetsuo、Maekawa Motoko、Toyota Tomoko、Dean Brian、Yoshikawa Takeo
  • Journal Title: Cerebral Cortex Volume: 31 Issue: 1 Pages: 448-462
  • DOI: 10.1093/cercor/bhaa236
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology. (2019)
  • Author(s): Ide M, et al. .... Kimura H, Yoshikawa T.
  • Journal Title: EMBO Mol Med. Volume: 11(12) Issue: 12
  • DOI: 10.15252/emmm.201910695
  • NAID: 120007132855
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Investigation of betaine as a novel psychotherapeutic for schizophrenia. (2019)
  • Author(s): Ohnishi T, Balan S, Toyoshima M, Maekawa M, Ohba H, Watanabe A, Iwayama Y, Fujita Y, Tan Y, Hisano Y, Shimamoto-Mitsuyama C, Nozaki Y, Esaki K, Nagaoka A, Matsumoto J, Hino M, Mataga N, Hayashi-Takagi A, Hashimoto K, Kunii Y, Kakita A, Yabe H, Yoshikawa T.
  • Journal Title: EBioMedicine Volume: 45 Pages: 432-446
  • DOI: 10.1016/j.ebiom.2019.05.062
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Evaluation of the role of fatty acid-binding protein 7 in controlling schizophrenia-relevant phenotypes using newly established knockout mice (2019)
  • Author(s): Shimamoto-Mitsuyama Chie、Ohnishi Tetsuo、Balan Shabeesh、Ohba Hisako、Watanabe Akiko、Maekawa Motoko、Hisano Yasuko、Iwayama Yoshimi、Owada Yuji、Yoshikawa Takeo
  • Journal Title: Schizophrenia Research Volume: - Pages: 52-59
  • DOI: 10.1016/j.schres.2019.02.002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Thiosulfate promotes hair growth in mouse model (2018)
  • Author(s): Maekawa Motoko、Ohnishi Tetsuo、Balan Shabeesh、Hisano Yasuko、Nozaki Yayoi、Ohba Hisako、Toyoshima Manabu、Shimamoto Chie、Tabata Chinatsu、Wada Yuina、Yoshikawa Takeo
  • Journal Title: Bioscience, Biotechnology, and Biochemistry Volume: 83 Issue: 1 Pages: 114-122
  • DOI: 10.1080/09168451.2018.1518705
  • Peer Reviewed / Int'l Joint Research
• [Presentation] DOHaD仮説を起点とした統合失調症病態メカニズムの解明 (2020)
  • Author(s): 前川素子
  • Organizer: 第50回日本神経精神薬理学会年会・第42回日本生物学的精神医学会年会・第4回日本精神薬学会総会・学術集会
• [Presentation] 脂肪酸結合タンパク質FABP4は自閉症の病態形成に関わる (2020)
  • Author(s): 前川
  • Organizer: 第125回日本解剖学会総会・全国学術集会
• [Presentation] Serum fatty acid-binding protein 4 as an early diagnostic biomarker for autism spectrum disorder (2019)
  • Author(s): 前川素子
  • Organizer: AsCNP (Asian College of Neuropsychopharmacology)
  • Int'l Joint Research
• [Presentation] 統合失調症の病態メカニズムにおける核内受容体 PPARα の役割 (2019)
  • Author(s): 和田唯奈, 大西哲生, 小林哲幸, 吉川武男, 前川素子
  • Organizer: 第46回日本脳科学会
• [Presentation] 核内受容体PPARαが統合失調症病態メカニズムにおいて果たす役割 (2019)
  • Author(s): 和田唯奈, 大西哲生, Balan Shabeesh, 岩山佳美, 大羽尚子, 渡邉明子, 久野泰子, 野崎弥生, 豊田倫子, 松岡茂, 岩本和也, 下郡智美, 糸川昌也, 小林哲幸, 吉川武男, 前川素子
  • Organizer: 第42回日本分子生物学会
• [Presentation] 神経発達期の多価不飽和脂肪酸欠乏による栄養学的統合失調症モデルマウスの検討 (2018)
  • Author(s): 前川素子、吉川武男
  • Organizer: 日本精神神経学会
• [Presentation] 脂肪酸・核内受容体に着目した自閉症及び統合失調症の研究 (2018)
  • Author(s): 前川素子
  • Organizer: 弘前大学
• [Presentation] こころの病気について考えよう (2018)
  • Author(s): 前川素子
  • Organizer: 世界脳週間2018 夏休み高校生理科教室