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; Chengfu Su; Jiahong Lu; Juxian Song; Min Li

doi:10.3390/ijms21041515

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, Chengfu Su, Jiahong Lu, Juxian Song, Min Li

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	1515
Journal	International journal of molecular sciences
Volume	21
Issue number	4
DOIs	https://doi.org/10.3390/ijms21041515
State	Published - Feb 2 2020
Externally published	Yes

Keywords

Curcumin derivatives
MTORC1
Parkinson’s disease
TFEB
α-synuclein

ASJC Scopus subject areas

Catalysis
Molecular Biology
Spectroscopy
Computer Science Applications
Physical and Theoretical Chemistry
Organic Chemistry
Inorganic Chemistry

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title = "A curcumin derivative activates TFEB and protects against parkinsonian neurotoxicity in vitro",

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{\textquoteright}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.",

keywords = "Curcumin derivatives, MTORC1, Parkinson{\textquoteright}s disease, TFEB, α-synuclein",

author = "Ziying Wang and Chuanbin Yang and Jia Liu and Tong, {Benjamin Chun Kit} and Zhou Zhu and Sandeep Malampati and Sreenivasmurthy, {Sravan Gopalkrishnashetty} and Cheung, {King Ho} and Ashok Iyaswamy and Chengfu Su and Jiahong Lu and Juxian Song and Min Li",

note = "Publisher Copyright: {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2020",

month = feb,

day = "2",

doi = "10.3390/ijms21041515",

language = "English (US)",

volume = "21",

journal = "International journal of molecular sciences",

issn = "1661-6596",

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T1 - A curcumin derivative activates TFEB and protects against parkinsonian neurotoxicity in vitro

AU - Wang, Ziying

AU - Yang, Chuanbin

AU - Liu, Jia

AU - Tong, Benjamin Chun Kit

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

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.

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KW - Parkinson’s disease

KW - TFEB

KW - α-synuclein

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A curcumin derivative activates TFEB and protects against parkinsonian neurotoxicity in vitro

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