2. Academic Validation
  3. A novel curcumin analog binds to and activates TFEB in vitro and in vivo independent of MTOR inhibition

A novel curcumin analog binds to and activates TFEB in vitro and in vivo independent of MTOR inhibition

  • Autophagy. 2016 Aug 2;12(8):1372-89. doi: 10.1080/15548627.2016.1179404.
Ju-Xian Song 1 2,  Yue-Ru Sun 3,  Ivana Peluso 4,  Yu Zeng 1 2,  Xing Yu 1 2,  Jia-Hong Lu 5,  Zheng Xu 3,  Ming-Zhong Wang 1,  Liang-Feng Liu 1 2,  Ying-Yu Huang 1 2,  Lei-Lei Chen 1 2,  Siva Sundara Kumar Durairajan 1 2,  Hong-Jie Zhang 1 2,  Bo Zhou 6,  Hong-Qi Zhang 1,  Aiping Lu 1,  Andrea Ballabio 4,  Diego L Medina 4,  Zhihong Guo 3,  Min Li 1 2
Affiliations

Affiliations

  • 1 a School of Chinese Medicine, Hong Kong Baptist University , Kowloon Tong, Hong Kong , China.
  • 2 b Mr. & Mrs. Ko Chi Ming Center for Parkinson Disease Research (CPDR), Hong Kong Baptist University , Kowloon Tong, Hong Kong , China.
  • 3 c Department of Chemistry , State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology , Clear Water Bay, Kowloon, Hong Kong , China.
  • 4 d Telethon Institute of Genetics and Medicine (TIGEM) , Naples , Italy.
  • 5 e State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau , Macau , China.
  • 6 f State Key Laboratory of Applied Organic Chemistry, Lanzhou University , Lanzhou , Gansu , China.
PMID: 27172265 DOI: 10.1080/15548627.2016.1179404
Abstract

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.

Keywords

autophagy; curcumin analogs; lysosomal biogenesis; mechanistic target of rapamycin; transcription factor EB.

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