Novel regulatory mechanism of Abeta degradation via ER stress
Project/Area Number |
17K19490
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Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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Allocation Type | Multi-year Fund |
Research Field |
Pharmaceutical Sciences and related fields
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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
|
Project Status |
Completed (Fiscal Year 2018)
|
Budget Amount *help |
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2018: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2017: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
|
Keywords | 小胞体ストレス / アルツハイマー病 / ユビキチン化 / Aβ / 小胞体 / ユビキチン / 細胞内局在 / 神経変性疾患 / Abeta |
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.
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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.
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Report
(3 results)
Research Products
(10 results)
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[Journal Article] Emerging role of electrophiles as a key regulator for endoplasmic reticulum (ER) stress.2019
Author(s)
Takasugi, N., Hiraoka, H., Nakahara, K., Akiyama, S., Fujikawa, K., Nomura, R., Furuichi, M., and Uehara, T.
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Journal Title
Int. J. Mol. Sci.
Volume: 20(7)
Issue: 7
Pages: 1783-1783
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Attenuation of macrophage migration inhibitory factor-stimulated signaling via S-nitrosylation.2019
Author(s)
Nakahara, K., Fujikawa, K., Hiraoka, H., Miyazaki, I., Asanuma, M., Ito, A., Takasugi, N., and Uehara, T.
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Journal Title
Biol. Pharm. Bull.
Volume: -
NAID
Related Report
Peer Reviewed / Open Access
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[Book] 実験医学2018
Author(s)
高杉展正,上原 孝
Total Pages
6
Publisher
羊土社
Related Report
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[Book] 脳神経化学2018
Author(s)
奥田洸作,高杉展正,上原 孝
Total Pages
10
Publisher
化学同人
Related Report
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