| Project/Area Number |
17K15621
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Pathological medical chemistry
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| Research Institution | Kyushu University |
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Principal Investigator |
Abe Yuichi 九州大学, 生体防御医学研究所, 学術研究員 (00529092)
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| Research Collaborator |
Fujiki Yukio
Honsho Masanori
Yamashita Toshihide
Ohgi Ryohei
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| Project Period (FY) |
2017-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | ペルオキシソーム / ペルオキシソーム形成異常症 / 小脳 / プルキンエ細胞 / 代謝障害 / 転写調節 / 脳神経疾患 / オルガネラ |
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| Outline of Final Research Achievements |
Peroxisome is a subcellular organelle essential for various metabolic reactions. Peroxisome biogenesis disorders (PBDs) manifest as neurological deficits in the brain, including abnormal cerebellum development. However, the mechanisms underlying pathogenesis remain enigmatic. In this research, we showed that ERK and AKT signaling are attenuated in peroxisome-deficient mouse by an elevated level of brain-derived neurotrophic factor (BDNF) together with the enhanced expression of TrkB-T1, a dominant-negative isoform of the BDNF receptor. This result suggests that dysregulation of the BDNF-TrkB pathway, an essential signaling for cerebellar morphogenesis, gives rise to the pathogenesis of cerebellum in PBDs. In addition, we revealed that the elevation of BDNF was induced by the cytosolic reductive state caused by the mislocalized catalase in peroxisome-deficient glia cells. Thus, our findings demonstrate for the first time the pathogenesis of PBDs.
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| Academic Significance and Societal Importance of the Research Achievements |
これまで、ペルオキシソーム形成異常症の病態発症機構に関して、分子レベルでの解明には至っていなかった。そんななか、我々の研究成果はBDNF-TrkBシグナル伝達系の異常が小脳形態異常の原因の一つであることを示し、世界で初めてペルオキシソーム形成異常症の病態発症機構を分子レベルで解明することに漕ぎ着けた。さらに、ペルオキシソーム欠損により誘発される細胞質還元化が及ぼす細胞機能への影響に関しても世界で初めての発見である。これらの成果は根本的な治療法が確立されていないペルオキシソーム形成異常症の治療法開発に繋がる可能性が高い。
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