Identification of a small molecule that induces autophagy-mediated degradation of TAU

2014 Fiscal Year Final Research Report

• Project/Area Number: 24241076
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Chemical biology
• Research Institution: Kyoto University
• Principal Investigator: HAGIWARA Masatoshi 京都大学, 医学(系)研究科(研究院), 教授 (10208423)
• 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)
• Project Period (FY): 2012-04-01 – 2015-03-31
• 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 / リン酸化酵素 / 急性ストレス

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.

Free Research Field

ケミカルバイオロジー