The Nrf2-NLRP3-caspase-1 axis mediates the neuroprotective effects of Celastrol in Parkinson's disease
Chenyu Zhang,
Miao Zhao,
Bingwei Wang,
Zhijie Su,
Bingbing Guo,
Lihua Qin,
Weiguang Zhang,
Ruimao Zheng
Affiliations
Chenyu Zhang
Department of Anatomy, Histology and Embryology, Health Science Center, Peking University, Beijing, China
Miao Zhao
Department of Anatomy, Histology and Embryology, Health Science Center, Peking University, Beijing, China
Bingwei Wang
Department of Anatomy, Histology and Embryology, Health Science Center, Peking University, Beijing, China
Zhijie Su
Department of Anatomy, Histology and Embryology, Health Science Center, Peking University, Beijing, China
Bingbing Guo
Department of Anatomy, Histology and Embryology, Health Science Center, Peking University, Beijing, China
Lihua Qin
Department of Anatomy, Histology and Embryology, Health Science Center, Peking University, Beijing, China
Weiguang Zhang
Department of Anatomy, Histology and Embryology, Health Science Center, Peking University, Beijing, China
Ruimao Zheng
Department of Anatomy, Histology and Embryology, Health Science Center, Peking University, Beijing, China; Neuroscience Research Institute, Peking University, Beijing, China; Key Laboratory for Neuroscience of Ministry of Education, Peking University, Beijing, China; Key Laboratory for Neuroscience of National Health Commission, Peking University, Beijing, China; Corresponding author. Department of Anatomy, Histology and Embryology, Health Science Center, Peking University, Beijing, China.
Parkinson's disease (PD) is a chronic neurodegenerative disorder that is characterized by motor symptoms as a result of a loss of dopaminergic neurons in the substantia nigra pars compacta (SNc), accompanied by chronic neuroinflammation, oxidative stress, formation of α-synuclein aggregates. Celastrol, a potent anti-inflammatory and anti-oxidative pentacyclic triterpene, has emerged as a neuroprotective agent. However, the mechanisms by which celastrol is neuroprotective in PD remain elusive. Here we show that celastrol protects against dopamine neuron loss, mitigates neuroinflammation, and relieves motor deficits in MPTP-induced PD mouse model and AAV-mediated human α-synuclein overexpression PD model. Whole-genome deep sequencing analysis revealed that Nrf2, NLRP3 and caspase-1 in SNc may be associated with the neuroprotective actions of celastrol in PD. By using multiple genetically modified mice (Nrf2-KO, NLRP3-KO and Caspase-1-KO), we identified that celastrol inhibits NLRP3 inflammasome activation, relieves motor deficits and nigrostriatal dopaminergic degeneration through Nrf2-NLRP3-caspase-1 pathway. Taken together, these findings suggest that Nrf2-NLRP3-caspase-1 axis may serve as a key target of celastrol in PD treatment, and highlight the favorable properties of celastrol for neuroprotection, making celastrol as a promising disease-modifying agent for PD.
