title: A novel curcumin analog binds to and activates TFEB in vitro and in vivo independent of MTOR inhibition.
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.
authors.affiliation: a School of Chinese Medicine, Hong Kong Baptist University , Kowloon Tong, Hong Kong , China.|b Mr. & Mrs. Ko Chi Ming Center for Parkinson Disease Research (CPDR), Hong Kong Baptist University , Kowloon Tong, Hong Kong , China.
authors.forename: Ju-Xian
authors.initials: JX
authors.lastname: Song
authors.affiliation: c Department of Chemistry , State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology , Clear Water Bay, Kowloon, Hong Kong , China.
authors.forename: Yue-Ru
authors.initials: YR
authors.lastname: Sun
authors.affiliation: d Telethon Institute of Genetics and Medicine (TIGEM) , Naples , Italy.
authors.forename: Ivana
authors.initials: I
authors.lastname: Peluso
authors.affiliation: a School of Chinese Medicine, Hong Kong Baptist University , Kowloon Tong, Hong Kong , China.|b Mr. & Mrs. Ko Chi Ming Center for Parkinson Disease Research (CPDR), Hong Kong Baptist University , Kowloon Tong, Hong Kong , China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: a School of Chinese Medicine, Hong Kong Baptist University , Kowloon Tong, Hong Kong , China.|b Mr. & Mrs. Ko Chi Ming Center for Parkinson Disease Research (CPDR), Hong Kong Baptist University , Kowloon Tong, Hong Kong , China.
authors.forename: Xing
authors.initials: X
authors.lastname: Yu
authors.affiliation: e State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau , Macau , China.
authors.forename: Jia-Hong
authors.initials: JH
authors.lastname: Lu
authors.affiliation: c Department of Chemistry , State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology , Clear Water Bay, Kowloon, Hong Kong , China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xu
authors.affiliation: a School of Chinese Medicine, Hong Kong Baptist University , Kowloon Tong, Hong Kong , China.
authors.forename: Ming-Zhong
authors.initials: MZ
authors.lastname: Wang
authors.affiliation: a School of Chinese Medicine, Hong Kong Baptist University , Kowloon Tong, Hong Kong , China.|b Mr. & Mrs. Ko Chi Ming Center for Parkinson Disease Research (CPDR), Hong Kong Baptist University , Kowloon Tong, Hong Kong , China.
authors.forename: Liang-Feng
authors.initials: LF
authors.lastname: Liu
authors.affiliation: a School of Chinese Medicine, Hong Kong Baptist University , Kowloon Tong, Hong Kong , China.|b Mr. & Mrs. Ko Chi Ming Center for Parkinson Disease Research (CPDR), Hong Kong Baptist University , Kowloon Tong, Hong Kong , China.
authors.forename: Ying-Yu
authors.initials: YY
authors.lastname: Huang
authors.affiliation: a School of Chinese Medicine, Hong Kong Baptist University , Kowloon Tong, Hong Kong , China.|b Mr. & Mrs. Ko Chi Ming Center for Parkinson Disease Research (CPDR), Hong Kong Baptist University , Kowloon Tong, Hong Kong , China.
authors.forename: Lei-Lei
authors.initials: LL
authors.lastname: Chen
authors.affiliation: a School of Chinese Medicine, Hong Kong Baptist University , Kowloon Tong, Hong Kong , China.|b Mr. & Mrs. Ko Chi Ming Center for Parkinson Disease Research (CPDR), Hong Kong Baptist University , Kowloon Tong, Hong Kong , China.
authors.forename: Siva Sundara Kumar
authors.initials: SS
authors.lastname: Durairajan
authors.affiliation: a School of Chinese Medicine, Hong Kong Baptist University , Kowloon Tong, Hong Kong , China.|b Mr. & Mrs. Ko Chi Ming Center for Parkinson Disease Research (CPDR), Hong Kong Baptist University , Kowloon Tong, Hong Kong , China.
authors.forename: Hong-Jie
authors.initials: HJ
authors.lastname: Zhang
authors.affiliation: f State Key Laboratory of Applied Organic Chemistry, Lanzhou University , Lanzhou , Gansu , China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhou
authors.affiliation: a School of Chinese Medicine, Hong Kong Baptist University , Kowloon Tong, Hong Kong , China.
authors.forename: Hong-Qi
authors.initials: HQ
authors.lastname: Zhang
authors.affiliation: a School of Chinese Medicine, Hong Kong Baptist University , Kowloon Tong, Hong Kong , China.
authors.forename: Aiping
authors.initials: A
authors.lastname: Lu
authors.affiliation: d Telethon Institute of Genetics and Medicine (TIGEM) , Naples , Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ballabio
authors.affiliation: d Telethon Institute of Genetics and Medicine (TIGEM) , Naples , Italy.
authors.forename: Diego L
authors.initials: DL
authors.lastname: Medina
authors.affiliation: c Department of Chemistry , State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology , Clear Water Bay, Kowloon, Hong Kong , China.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Guo
authors.affiliation: a School of Chinese Medicine, Hong Kong Baptist University , Kowloon Tong, Hong Kong , China.|b Mr. & Mrs. Ko Chi Ming Center for Parkinson Disease Research (CPDR), Hong Kong Baptist University , Kowloon Tong, Hong Kong , China.
authors.forename: Min
authors.initials: M
authors.lastname: Li
mesh_terms: D000818:Animals; D001343:Autophagy; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003474:Curcumin / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D019636:Neurodegenerative Diseases / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C064972:TFEB protein, human; C574124:TFEB protein, rat; C484068:Tcfeb protein, mouse; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D003474:Curcumin
keywords: autophagy; curcumin analogs; lysosomal biogenesis; mechanistic target of rapamycin; transcription factor EB