| Project/Area Number |
17K07041
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Neurophysiology / General neuroscience
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| Research Institution | University of Tsukuba |
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Principal Investigator |
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | ショウジョウバエ / 統合失調症 / DISC1 / シナプス / NRX1 / FMR1 / 自閉症 / 遺伝学 / 精神疾患 / リスク遺伝子 / 脳 |
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| Outline of Final Research Achievements |
Originally identified at the breakpoint of a (1;11)(q42.1; q14.3) chromosomal translocation in a Scottish family with a wide range of mental disorders, the DISC1 gene has been a focus of intensive investigations as an entry point to study the molecular mechanisms of diverse mental dysfunctions. In this work, we have expressed the human DISC1 gene in the fruit fly and performed a genetic screening for the mutations of psychiatric risk genes that cause modifications of DISC1 synaptic phenotypes at neuromuscular junctions. We found that DISC1 interacts with dnrx1, the Drosophila homolog of the human Neurexin (NRXN1) gene, and dFMR1 in the development of glutamatergic synapses. Given that both NRX1 and FMR1 have been identified as risk factor genes for diverse psychiatric disorders including schizophrenia and autism spectrum disorders, our results suggest an intriguing converging mechanism controlled by DISC1, Neurexin, and FMR1.
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| Academic Significance and Societal Importance of the Research Achievements |
統合失調症患者の大規模伝子関連解析により、多数のリスク遺伝子が同定され、発症機構の遺伝的要因の解明に重要な手がかりが得られつつある。しかしながら、個々の遺伝子の疾患リスクに対する効果は限定的であり、複数の遺伝子に対する多重変異体を用いた神経遺伝学的メカニズムの解明が必須の課題である。本研究では、DISC1遺伝子と自閉症関連遺伝子Neurexin１及びFMR１がシナプス形成過程において相互作用することを明らかにした。これらの結果は、統合失調症発症機構におけるシナプス仮説を支持すると共に、臨床的に異なる二つの精神疾患に共通の分子メカニズムが存在することを示唆している。
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