Lipid flippase is the novel therapeutic target for the Alzheimer disease, which correlate with endocytic traffic impairment.
Project/Area Number |
17K08272
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Research Field |
Biological pharmacy
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Research Institution | Okayama University |
Principal Investigator |
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Co-Investigator(Kenkyū-buntansha) |
橋本 唯史 東京大学, 大学院医学系研究科(医学部), 特任准教授 (30334337)
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Project Period (FY) |
2017-04-01 – 2020-03-31
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Project Status |
Completed (Fiscal Year 2019)
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Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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Keywords | アルツハイマー / リピッドフリッパーゼ / 小胞輸送 / アルツハイマー病 / アミロイドβ |
Outline of Final Research Achievements |
Although Amyloid beta (Aβ) peptide, which accumulates in Alzheimer disease (AD) brain, is focused attention as a therapeutic target, most clinical trials are failed. Interestingly, endocytic dysfunction is the early pathogenic event by the accumulation of Aβ precursor protein (APP) metabolites, β-carboxyl-terminal fragment (βCTF). We identified TMEM30A, a subcomponent of lipid flippase, as a candidate partner for βCTF. Moreover, stably overexpression of β-site APP cleaving enzyme 1 (BACE1) accumulated βCTF to increase the complex with TMEM30A. Intriguingly, upregulated BACE1 activity reduced both the lipid flippase formation and activity, which was accompanied by the abnormally enlarged endosomes. We confirmed the complex formation of TMEM30A and βCTF, and lipid flippase dysfunction in AD model mice before Aβ deposition. Our results shed light on the unidentified correlation between βCTF and lipid flippase activity and suggest a novel therapeutic strategy for AD.
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Academic Significance and Societal Importance of the Research Achievements |
アルツハイマー病では小胞輸送障害は最初期病態の一つであり,その予防・根本治療法開発の鍵を握る.一方で,小胞輸送の状態について,定量的かつ網羅的な解析を行う手段は限られており,詳細な分子メカニズムの解明,小胞輸送障害を標的とした根治療法の開発がこれまで困難であった. 本研究ではアルツハイマー病における小胞輸送障害の制御因子としてリピッドフリッパーゼを同定しており,小胞輸送を標的とした根本治療薬の開発という新しい分野を開拓の短所となることが期待される.また本研究により樹立された解析系は,タンパク質の局在の定量的な解析に応用でき,当該分野の研究発展に応用可能である.
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Report
(4 results)
Research Products
(17 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] Modulation of Unfolded Protein Response by Methylmercury2017
Author(s)
Hiraoka H, Nakahara K, Kaneko Y, Akiyama S, Okuda K, Iwawaki T, Fujimura M, Kumagai Y, Takasugi N, Uehara T.
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Journal Title
Biological and Pharmaceutical Bulletin
Volume: 40
Issue: 9
Pages: 1595-1598
DOI
NAID
ISSN
0918-6158, 1347-5215
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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