Novel approaches to drug development of schizophrenia

2022 Fiscal Year Final Research Report

• 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 (2021-2022); 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
• 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

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.

Free Research Field

分子精神医学

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。