1. RIP1/RIP3/MLKL mediates dopaminergic neuron necroptosis in a mouse model of Parkinson disease
- Author
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Yuanxiang Lin, Wei-Xiong Wang, Yan-Fang Xu, Liang-Hong Yu, Dezhi Kang, Qing-Song Lin, Ping Chen, Chen-Chao Lin, and Yao Zhou
- Subjects
Male ,0301 basic medicine ,Necroptosis ,Biology ,Pathology and Forensic Medicine ,Proinflammatory cytokine ,Pathogenesis ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Downregulation and upregulation ,Dopamine ,medicine ,Animals ,Molecular Biology ,Dopaminergic Neurons ,MPTP ,Dopaminergic ,Parkinson Disease ,Cell Biology ,Cell biology ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,nervous system ,chemistry ,1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ,Apoptosis ,Receptor-Interacting Protein Serine-Threonine Kinases ,030220 oncology & carcinogenesis ,Cytokines ,Protein Kinases ,medicine.drug - Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disorder and is characterized by severe neuronal loss. Necroptosis, or programmed cell necrosis, is mediated by the receptor interacting protein kinase-1 and -3/mixed lineage kinase domain-like protein (RIP1/RIP3/MLKL) pathway, and is involved in several neurodegenerative diseases. Here we aimed to explore the involvement of necroptosis in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine hydrochloride (MPTP)-induced PD and determine the potential mechanisms. We found that the protein levels of RIP1, RIP3, and MLKL increased significantly in a MPTP-induced mouse PD model. High expression of RIP1/RIP3/MLKL was associated with severe loss of dopaminergic neurons. Pretreatment with necrostatin-1 or the knockout of the RIP3/MLKL gene to block necroptosis pathway dramatically ameliorated PD by increasing dopamine levels and rescuing the loss of dopaminergic neurons, independent of the apoptotic pathway. Moreover, upregulation of inflammatory cytokines in MPTP-treated mice was partially inhibited by deletion of RIP3 or MLKL gene, indicating that a positive feedback loop exists between these genes and inflammatory cytokines. Our data indicate that RIP1/RIP3/MLKL-mediated necroptosis is involved in the pathogenesis of MPTP-induced PD. Downregulating the expression of RIP1, RIP3, or MLKL can significantly attenuate MPTP-induced PD. Future therapy targeting necroptosis may be a promising new option.
- Published
- 2020