A Curcumin Derivative Activates TFEB and Protects Against Parkinsonian Neurotoxicity in Vitro

• Main Authors: Ziying Wang, Chuanbin Yang, Jia Liu, Benjamin Chun-Kit Tong, Zhou Zhu, Sandeep Malampati, Sravan Gopalkrishnashetty Sreenivasmurthy, King-Ho Cheung, Ashok Iyaswamy, Chengfu Su, Jiahong Lu, Juxian Song, Min Li
• Format: Article
• Language: English
• Published: MDPI AG 2020-02-01
• Series: International Journal of Molecular Sciences
• Subjects: tfeb; parkinson’s disease; α-synuclein; curcumin derivatives; mtorc1
• Online Access: https://www.mdpi.com/1422-0067/21/4/1515
• ISSN: 1422-0067

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.