A Curcumin Derivative Activates TFEB and Protects Against Parkinsonian Neurotoxicity in Vitro
Ziying Wang, Chuanbin Yang, Jia Liu, Benjamin Chun‐Kit Tong, Zhou Zhu, Sandeep Malampati, Sravan Gopalkrishnashetty Sreenivasmurthy, King‐Ho Cheung, Ashok Iyaswamy, Cheng-Fu Su, Jiahong Lu, Ju‐Xian Song, Min Li
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’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 α-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.