Basic research for the development of therapeutic drugs for Alzheimer's disease targeting a novel ubiquitin ligase

• Project/Area Number: 18K06855
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48020:Physiology-related
• Research Institution: Kochi University
• Principal Investigator: Yasukawa Takashi 高知大学, 教育研究部医療学系基礎医学部門, 助教 (60291936)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: アルツハイマー病 / ユビキチンリガーゼ / NRBP1 / BRI2 / BRI3 / アミロイドβ

Outline of Final Research Achievements

Alzheimer's disease (AD) is a progressive neurodegenerative disease caused by accumulations of Aβpeptides. Production and fibrillation of Aβ are downregulated by BRI2 and BRI3, which are physiological inhibitors of amyloid precursor protein (APP) processing and Aβ oligomerization. We identify nuclear receptor binding protein 1 (NRBP1) as a substrate receptor of a Cullin-RING ubiquitin ligase (CRL) that targets BRI2 and BRI3 for degradation. Furthermore,NRBP1 knockdown in neuronal cells results in an increase in the abundance of BRI2 and BRI3 and significantly reduces Aβ production. Thus, disrupting interactions between NRBP1 and its substrates BRI2 and BRI3 may provide a useful therapeutic strategy for AD.
We therefore set out to develop a screening system for the discovery of inhibitors.

Academic Significance and Societal Importance of the Research Achievements

まだ詳細な機能がよく分かっていないNRBP1が、基質認識タンパク質として2量体化してCul2ならびにCul4Aと結合してヘテロ2量体型のユビキチンリガーゼ複合体を形成、抗アルツハイマー病因子であるBRI2/BRI3を選択的にユビキチン化して分解に導くことを明らかにした。そして、NRBP1-ユビキチンリガーゼと基質BRI2/BRI3間の相互作用を阻害する化合物が、細胞内BRI2/BRI3のタンパク質量を増加させることで両因子のもつ抗AD作用を増強する新規アルツハイマー病治療薬になり得る可能性があることを示した。

Research Products

• [Journal Article] NRBP1-Containing CRL2/CRL4A Regulates Amyloid β Production by Targeting BRI2 and BRI3 for Degradation (2020)
  • Author(s): Yasukawa T, Tsutsui A, Tomomori-Sato C, Sato S, Saraf A, Washburn MP, Florens L, Terada T, Shimizu K, Conaway RC, Conaway JW, Aso T.
  • Journal Title: Cell Reports Volume: 30 Issue: 10 Pages: 3478-3491
  • DOI: 10.1016/j.celrep.2020.02.059
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Remarks] 講座紹介 遺伝子機能解析学
  • URL: http://www.kochi-ms.ac.jp/html/gakubu/fg_chmst.html
• [Remarks] アルツハイマー病創薬への応用が期待される新たな酵素複合体を発見
  • URL: http://www.kochi-ms.ac.jp/html/news/2019/functionalgenomics2019-1.html
• [Patent(Industrial Property Rights)] 認知症治療薬のスクリーニング方法 (2019)
  • Inventor(s): 麻生 悌二郎、安川 孝史
  • Industrial Property Rights Holder: 麻生 悌二郎、安川 孝史
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2019-088444
  • Filing Date: 2019