Novel regulatory mechanism of Abeta degradation via ER stress

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K19490
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Pharmaceutical Sciences and related fields
• Research Institution: Okayama University
• Principal Investigator: Uehara Takashi 岡山大学, 医歯薬学総合研究科, 教授 (00261321)
• Project Period (FY): 2017-06-30 – 2019-03-31
• Keywords: 小胞体ストレス / アルツハイマー病 / ユビキチン化

Outline of Final Research Achievements

To clarify the role of E3 ligase that is involved in ER stress signaling, we attempted to find its substrate. In this study, we succeeded in identifying an Aβ degrading enzymes (proteases). The substrate protein was polyubiquitinated but not degraded by proteasome. Next, we examined if ubiquitination results in the change in the enzymatic activity. Hydrolysis of Aβ peptide was significantly suppressed by this modification. Therefore, it is suggested that under the endoplasmic reticulum stress environment, an E3 ligases is highly expressed, and ubiquitination of the substrate may alter intracellular localization by regulating the enzyme activity.

Free Research Field

神経薬理学

Academic Significance and Societal Importance of the Research Achievements

これまでに，小胞体ストレスとAβ蓄積との因果関係を明らかにした研究はない．本研究において，小胞体ストレス依存的に発現が上昇するユビキチンE3リガーゼがAβ水解酵素を基質として，その酵素活性に影響を及ぼすことを見出した．この現象が，ヒトアルツハイマー病発症に連関するかどうか，今後ヒト死後脳などを使用して検証していく予定である．これが証明されれば，創薬の標的になり得る可能性がある．