1. A Curcumin Derivative Activates TFEB and Protects Against Parkinsonian Neurotoxicity in Vitro
- Author
-
Zi-Ying Wang, Zhou Zhu, Min Li, Cheng-Fu Su, Sandeep Malampati, Jia Liu, Sravan Gopalkrishnashetty Sreenivasmurthy, Jia-Hong Lu, Ju-Xian Song, Chuanbin Yang, King-Ho Cheung, Benjamin Chun-Kit Tong, and Ashok Iyaswamy
- Subjects
1-Methyl-4-phenylpyridinium ,mTORC1 ,PC12 Cells ,lcsh:Chemistry ,chemistry.chemical_compound ,lcsh:QH301-705.5 ,Spectroscopy ,Neurons ,Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ,Neurodegenerative Diseases ,Parkinson Disease ,General Medicine ,Computer Science Applications ,Cell biology ,medicine.anatomical_structure ,alpha-Synuclein ,RNA Interference ,Signal Transduction ,Curcumin ,Cell Survival ,Active Transport, Cell Nucleus ,Neuroprotection ,Article ,Catalysis ,Inorganic Chemistry ,α-synuclein ,Cell Line, Tumor ,Lysosome ,Autophagy ,medicine ,Animals ,Humans ,Physical and Theoretical Chemistry ,Molecular Biology ,Curcumin derivatives ,MTORC1 ,TFEB ,Activator (genetics) ,Organic Chemistry ,Rats ,lcsh:Biology (General) ,lcsh:QD1-999 ,chemistry ,Parkinson’s disease ,Lysosomes ,Biogenesis ,HeLa Cells - Abstract
TFEB (transcription factor EB), which is a master regulator of autophagy and lysosome biogenesis, is considered to be a new therapeutic target for Parkinson&rsquo, s disease (PD). However, only several small-molecule TFEB activators have been discovered and their neuroprotective effects in PD are unclear. In this study, a curcumin derivative, named E4, was identified as a potent TFEB activator. Compound E4 promoted the translocation of TFEB from cytoplasm into nucleus, accompanied by enhanced autophagy and lysosomal biogenesis. Moreover, TFEB knockdown effectively attenuated E4-induced autophagy and lysosomal biogenesis. Mechanistically, E4-induced TFEB activation is mainly through AKT-MTORC1 inhibition. In the PD cell models, E4 promoted the degradation of &alpha, synuclein and protected against the cytotoxicity of MPP+ (1-methyl-4-phenylpyridinium ion) in neuronal cells. Overall, the TFEB activator E4 deserves further study in animal models of neurodegenerative diseases, including PD.
- Published
- 2020
- Full Text
- View/download PDF