Identification of a small molecule that induces autophagy-mediated degradation of TAU
| Project/Area Number |
24241076
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Chemical biology
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| Research Institution | Kyoto University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
NINOMIYA Kensuke 京都大学, 医学研究科, 助教 (00437279)
HOSOYA Takamitsu 東京医科歯科大学, 生体材料工学研究所, 教授 (60273124)
KATAOKA Naoyuki 京都大学, 大学院医学研究科, 准教授 (60346062)
TAKEUCHI Akihide 京都大学, 大学院医学研究科, 准教授 (90436618)
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| Project Period (FY) |
2012-04-01 – 2015-03-31
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| Project Status |
Completed (Fiscal Year 2014)
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| Budget Amount *help |
¥47,450,000 (Direct Cost: ¥36,500,000、Indirect Cost: ¥10,950,000)
Fiscal Year 2014: ¥13,780,000 (Direct Cost: ¥10,600,000、Indirect Cost: ¥3,180,000)
Fiscal Year 2013: ¥13,520,000 (Direct Cost: ¥10,400,000、Indirect Cost: ¥3,120,000)
Fiscal Year 2012: ¥20,150,000 (Direct Cost: ¥15,500,000、Indirect Cost: ¥4,650,000)
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| Keywords | タウオパチー / アルツハイマー病 / 化合物 / スクリーニング / タウ / リン酸化酵素 / 急性ストレス / 神経変性疾患 / アルツハイマー / FTDP-17 / ストレス / 細胞 / DYRK1A / 低分子化合物 / ハイスループット |
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| Outline of Final Research Achievements |
Aberrant accumulation of TAU has been recognized as one of characteristic features in neurodegenerative diseases known as tauopathies, which include Alzheimer's disease. Deletion of Tau-encoding Mapt in mice prevented Amyloid-beta-mediated deficits, suggesting that reducing Tau protein confers resistance to Amyloid-beta-mediated neurodegeneration. In this study, we developed a cell-based assay system based on doxycycline-driven bicistronic expression of mCherry and TAU fused with EGFP, in order to evaluate effects of molecules on TAU protein. We identified a small molecule that induces degradation of TAU. This compound, FIT-068, decreased not only endogenous, but also mutant TAU proteins harboring genetic mutations of hereditary tauopathies. FIT-068-mediated decrease of TAU was prevented by pre-treatment with an inhibitor of lysosomal degradation, suggesting that FIT-068 induces autophagy-mediated degradation of TAU. FIT-068 is thus a promising drug candidate for treating tauopathies.
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Report
(4 results)
Research Products
(38 results)
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[Journal Article] Rectifier of aberrant mRNA splicing recovers tRNA modification in familial dysautonomia.2015
Author(s)
Yoshida M, Kataoka N, Miyauchi K, Ohe K, Iida K, Yoshida S, Nojima T, Okuno Y, Onogi H, Usui T, Takeuchi A, Hosoya T, Suzuki T, Hagiwara M.
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Journal Title
Proc Natl Acad Sci U S A.
Volume: 112（9）
Issue: 9
Pages: 2764-2769
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] RBFOX and SUP-12 sandwich a guanine base to form a stable complex and regulate tissue-specific splicing.2014
Author(s)
Kuwasako K, Takahashi M, Unzai S, Tsuda K, Yoshikawa S, He F, Kobayashi N, Guntert P, Shirouzu M, Ito T, Tanaka A, Yokoyama S, Hagiwara M, Kuroyanagi H, and Muto Y.
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Journal Title
Nat. Struct. Mol. Biol.
Volume: 21(9)
Issue: 9
Pages: 778-86
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Topical antiangiogenic SRPK1 inhibitors reduce choroidal neovascularization in rodent models of exudative AMD.2013
Author(s)
Gammons MV, Fedorov O, Ivison D, Du C, Clark T, Hopkins C, Hagiwara M, Dick AD, Cox R, Harper SJ, Hancox JC, Knapp S, Bates DO.
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Journal Title
Invest Ophthalmol Vis Sci.
Volume: 54(9)
Issue: 9
Pages: 6052-6062
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Inhibition of DYRK1A destabilizes EGFR and reduces EGFR-dependent glioblastoma growth2013
Author(s)
Pozo N, Zahonero C, Fernández P, Liñares JM, Ayuso A, Hagiwara M, Pérez A, Ricoy JR, Hernández-Laín A, Sepúlveda JM, Sánchez-Gómez P.
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Journal Title
J Clin Invest.
Volume: 123(6)
Issue: 6
Pages: 2475-2487
DOI
Related Report
Peer Reviewed / Open Access
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