PARP1 promotes NLRP3 activation via blocking TFEB-mediated autophagy in rotenone-induced neurodegeneration

He Zhang; Zhefan Xie; Yongming Peng; Ailun Xie; Chunlai Fu; Dongyan Zheng; ZiWei Cai; Jiahong Zhong; Qiang Ming; Mingque Li; Renjian Lu; Xin Liu; Jialong Chen

doi:10.1016/j.ecoenv.2023.114630

PARP1 promotes NLRP3 activation via blocking TFEB-mediated autophagy in rotenone-induced neurodegeneration

Ecotoxicol Environ Saf. 2023 Mar 1:252:114630. doi: 10.1016/j.ecoenv.2023.114630. Epub 2023 Feb 8.

Authors

He Zhang¹, Zhefan Xie², Yongming Peng³, Ailun Xie³, Chunlai Fu², Dongyan Zheng³, ZiWei Cai³, Jiahong Zhong⁴, Qiang Ming⁵, Mingque Li³, Renjian Lu³, Xin Liu⁶, Jialong Chen⁷

Affiliations

¹ Department of Preventive Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, PR China; Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, PR China. Electronic address: zhangh@gdmu.edu.cn.
² Department of Emergency Intensive Care Unit, Affiliated Dongguan People's Hospital, Southern Medical University, Dongguan, Guangdong, PR China.
³ Department of Preventive Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, PR China; Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, PR China.
⁴ Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 528400, PR China.
⁵ Department of Neurology, Longgang Central Hospital of Shenzhen, 518116, PR China.
⁶ Department of Preventive Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, PR China; Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, PR China. Electronic address: lx@gdmu.edu.cn.
⁷ Department of Preventive Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, PR China; Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan 523808, PR China. Electronic address: jialongc@gdmu.edu.cn.

PMID: 36764072
DOI: 10.1016/j.ecoenv.2023.114630

Abstract

Rotenone, a widely used pesticide, causes dopaminergic neurons loss and increase the risk of Parkinson's disease (PD). However, few studies link the role of PARP1 to neuroinflammatory response and autophagy dysfunction in rotenone-induced neurodegeneration. Here, we identified that PARP1 overactivation caused by rotenone led to autophagy dysfunction and NLRP3-mediated inflammation. Further results showed that PARP1 inhibition could reduce NLRP3-mediated inflammation, which was effectively eliminated by TFEB knockdown. Moreover, PARP1 poly(ADP-ribosyl)ated TFEB that reduced autophagy. Of note, PARP1 inhibition could rescue rotenone-induced dopaminergic neurons loss. Overall, our study revealed that PARP1 blocks autophagy through poly (ADP-ribosyl)ating TFEB and inhibited NLRP3 degradation, which suggests that intervention of PARP1-TFEB-NLRP3 signaling can be a new treatment strategy for rotenone-induced neurodegeneration.

Keywords: Autophagy; NLRP3; PARP1; Rotenone; TFEB.

MeSH terms

Autophagy
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / pharmacology
Humans
Inflammation
NLR Family, Pyrin Domain-Containing 3 Protein / genetics
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
Parkinson Disease* / genetics
Parkinson Disease* / metabolism
Poly (ADP-Ribose) Polymerase-1 / genetics
Rotenone* / toxicity

Substances

Rotenone
NLR Family, Pyrin Domain-Containing 3 Protein
TFEB protein, human
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
PARP1 protein, human
Poly (ADP-Ribose) Polymerase-1