期刊
AUTOPHAGY
卷 12, 期 8, 页码 1372-1389出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2016.1179404
关键词
autophagy; curcumin analogs; lysosomal biogenesis; mechanistic target of rapamycin; transcription factor EB
类别
资金
- Hong Kong General Research Fund [RGC/HKBU-121009/14]
- Research Grants Council & Natural Science Foundation Council of China [RGC-N_HKBU 213/11, N_HKUST621/13]
- Innovation and Technology Fund (ITF) of Hong Kong Government [ITS/274/12]
- Interdisciplinary Research Matching Scheme (IRMS) [IRMS/12-13/1A]
- Matching Proof-of-Concept Fund (MPCF) [MPCF 04-12/13, MPCF-008-2014/2015]
- Hong Kong Baptist University [38-40-183]
- Natural Science Foundation of China [21172101]
Autophagy dysfunction is a common feature in neurodegenerative disorders characterized by accumulation of toxic protein aggregates. Increasing evidence has demonstrated that activation of TFEB (transcription factor EB), a master regulator of autophagy and lysosomal biogenesis, can ameliorate neurotoxicity and rescue neurodegeneration in animal models. Currently known TFEB activators are mainly inhibitors of MTOR (mechanistic target of rapamycin [serine/threonine kinase]), which, as a master regulator of cell growth and metabolism, is involved in a wide range of biological functions. Thus, the identification of TFEB modulators acting without inhibiting the MTOR pathway would be preferred and probably less deleterious to cells. In this study, a synthesized curcumin derivative termed C1 is identified as a novel MTOR-independent activator of TFEB. Compound C1 specifically binds to TFEB at the N terminus and promotes TFEB nuclear translocation without inhibiting MTOR activity. By activating TFEB, C1 enhances autophagy and lysosome biogenesis in vitro and in vivo. Collectively, compound C1 is an orally effective activator of TFEB and is a potential therapeutic agent for the treatment of neurodegenerative diseases.
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