Molecular pathogenesis of neurological diseases caused by disruption of early Golgi quality control system

2020 Fiscal Year Final Research Report

• Project/Area Number: 17K08621
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Waseda University
• Principal Investigator: Hara Taichi 早稲田大学, 人間科学学術院, 教授 (00392374)
• Project Period (FY): 2017-04-01 – 2021-03-31
• 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

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.

Free Research Field

細胞生物学, 食品科学

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。