TY - JOUR
T1 - A curcumin derivative activates TFEB and protects against parkinsonian neurotoxicity in vitro
AU - Wang, Ziying
AU - Yang, Chuanbin
AU - Liu, Jia
AU - Tong, Chun Kit Benjamin
AU - Zhu, Zhou
AU - Malampati, Sandeep
AU - Sreenivasmurthy, Sravan Gopalkrishnashetty
AU - Cheung, King Ho
AU - Iyaswamy, Ashok
AU - Su, Chengfu
AU - Lu, Jiahong
AU - Song, Juxian
AU - Li, Min
N1 - Funding Information:
Funding: This study was supported by Shenzhen Science and Technology Innovation Commission (SZSTI, 201803023000787), (JCYJ, 20180302174028790) and (JCYJ20180507184656626). the National Natural Science Foundation of China (81703487, 81773926), the General Research Fund (GRF/HKBU12101417, GRF/HKBU12100618), and the Hong Kong Health and Medical Research Fund (HMRF14150811, HMRF15163481) from Hong Kong Government, and research funds (HKBU/RC-IRCs/17-18/03, HKBU/RC-IRMS/15-16/04, FRGI/17-18/041, FRGII/17-18/021) from Hong Kong Baptist University.
Funding Information:
We would like to thank Prof. Richard J. Youle (National Institute of Neurological Disorders and Stroke) and Prof. Myung-Shik Lee (Yonsei University College of Medicine) for providing TFEB knock out Hela cells. We thank Tamotsu Yoshimori (Osaka University) for providing the tfLC3 plasmid. We would like to thank for Dr. Carol Chu?s support and assistant. We would like to thank Dr. Martha Dahlen for her English editing. Funding: This study was supported by Shenzhen Science and Technology Innovation Commission (SZSTI, 201803023000787), (JCYJ, 20180302174028790) and (JCYJ20180507184656626). the National Natural Science Foundation of China (81703487, 81773926), the General Research Fund (GRF/HKBU12101417, GRF/HKBU12100618), and the Hong Kong Health and Medical Research Fund (HMRF14150811, HMRF15163481) from Hong Kong Government, and research funds (HKBU/RC-IRCs/17-18/03, HKBU/RC-IRMS/15-16/04, FRGI/17-18/041, FRGII/17-18/021) from Hong Kong Baptist University.
PY - 2020/2/2
Y1 - 2020/2/2
N2 - 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.
AB - 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.
KW - Curcumin derivatives
KW - MTORC1
KW - Parkinson’s disease
KW - TFEB
KW - α-synuclein
UR - http://www.scopus.com/inward/record.url?scp=85079840772&partnerID=8YFLogxK
U2 - 10.3390/ijms21041515
DO - 10.3390/ijms21041515
M3 - Journal article
C2 - 32098449
AN - SCOPUS:85079840772
SN - 1661-6596
VL - 21
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 4
M1 - 1515
ER -
