Molecular pathogenesis of neurological diseases caused by disruption of early Golgi quality control system
| Project/Area Number |
17K08621
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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 |
General medical chemistry
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| Research Institution | Waseda University |
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Principal Investigator |
Hara Taichi 早稲田大学, 人間科学学術院, 教授 (00392374)
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| Project Period (FY) |
2017-04-01 – 2021-03-31
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| Project Status |
Discontinued (Fiscal Year 2020)
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| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2020: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | γセクレターゼ / Notchシグナル / 初期ゴルジ / Rer1 / 細胞膜タンパク質 / タンパク質品質管理 / 神経幹細胞 / 大脳形成 / 神経難病 / 大脳発生 / ゴルジ体 / γ-secretase / リソソーム / 膜タンパク質 / 脳神経疾患 / 細胞・組織 / 発生・分化 / 蛋白質 |
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| Outline of Final Research Achievements |
Rer1 is a retrieval receptor for endoplasmic reticulum (ER) retention of various ER membrane proteins and unassembled or immature components of membrane protein complexes. We show that Rer1 is required for the sufficient cell surface expression and activity of γ-secretase complex, which modulates Notch signaling during mouse cerebral cortex development. When Rer1 was depleted in the mouse cerebral cortex, the number of neural stem cells decreased significantly, and malformation of the cerebral cortex was observed. In Rer1-deficient cells, a subpopulation of γ-secretase complexes and components was transported to and degraded in lysosomes, thereby significantly reducing the amount of γ-secretase complex on the cell surface. These results suggest that Rer1 maintains Notch signaling by maintaining sufficient expression of the γ-secretase complex on the cell surface and regulating neural stem cell maintenance during cerebral cortex development.
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| Academic Significance and Societal Importance of the Research Achievements |
γ-セクレターゼはアルツハイマー病の原因の１つであるβアミロイドの産生に働くことが知られています。また、個体発生や幹細胞維持に機能するNotchシグナルの異常は、神経疾患やガンを含めた様々な疾患を引き起こすことが知られています。このことから、今回の成果は、γ-セクレターゼや幹細胞の関係する疾患の発症機構の解明や治療法開発への応用が期待できます。
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Report
(4 results)
Research Products
(9 results)
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[Journal Article] Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy2018
Author(s)
Higuchi Yujiro、Ohtake Akira、Matsuura Eiji、Ueda Takehiro、Toda Tatsushi、Yamashita Sumimasa、Yamada Kenichiro、Koide Takashi、Yaguchi Hiroaki、Mitsui Jun、Ishiura Hiroyuki、Yoshimura Jun、Doi Koichiro、Morishita Shinichi、Sato Ken、Nakagawa Masanori、Yamaguchi Masamitsu、Tsuji Shoji、Takashima Hiroshi
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Journal Title
Brain
Volume: 印刷中
Issue: 6
Pages: 1622-1636
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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