Basic study for development of novel anti-dementia drug which selectively targets BRI2/3-ubiquitin ligase

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K06959
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Kochi University
• Principal Investigator: Aso Teijiro 高知大学, 教育研究部医療学系基礎医学部門, 教授 (20291289)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 認知症 / アルツハイマー病 / ユビキチンリガーゼ / NRBP1 / BRI2/ITM2 / BRI3/ITM2C / Cullin-RING ligase / Elongin

Outline of Final Research Achievements

Production and fibrillation of Amyloid beta (Abeta) are down-regulated by BRI2 and BRI3, which are physiological inhibitors of amyloid precursor protein (APP) processing and Abeta oligomerization. Here, we identify NRBP1 as a substrate receptor of a Cullin-RING ubiquitin ligase (CRL) that targets BRI2 and BRI3 for degradation. Moreover, we demonstrate that (i) dimerized NRBP1 assembles into a functional Cul2- and Cul4A-containing heterodimeric CRL through its BC-box and an overlapping cryptic H-box, (ii) both Cul2 and Cul4A contribute to NRBP1 CRL function, and (iii) formation of the NRBP1 heterodimeric CRL is strongly enhanced by chaperone-like function of TSC22D3 and TSC22D4. NRBP1 knockdown in neuronal cells resulted in an increase in the abundance of BRI2 and BRI3, and significantly reduced Abeta production. Thus, disrupting interactions between NRBP1 and its substrates BRI2 and BRI3 may provide a useful therapeutic strategy for AD.

Free Research Field

病態医化学

Academic Significance and Societal Importance of the Research Achievements

学術的意義：NRBP1のBC-boxに重複してDDB1の結合配列H-boxが存在することを見出し、ホモ二量体化したNRBP1がBC-box、H-boxを介してそれぞれCul2、Cul4Aと結合、ヘテロ二量体構造のCullin-RING型E3を形成することを世界で初めて示した。さらに、①基質の高度のUb化に当該E3の非対称な構造が有利に働くこと、②他の多くの基質認識タンパク質のBC-boxにもH-boxが重複して存在することを示した。
社会的意義：NRBP1とBRI2/BRI3間の相互作用の阻害は、両因子機能の人為的な活性化に繋がり、アルツハイマー病に対する根本治療薬の開発に資する可能性を示した。