RIP1/RIP3/MLKL mediates dopaminergic neuron necroptosis in a mouse model of Parkinson disease

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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.

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We would like to thank Institute of Neurology and Central laboratory of First Affiliated Hospital of Fujian Medical University for their kind support and technical guidance in conducting this study. This study was sponsored by key clinical specialty discipline construction program of Fujian, P.R.C. (No. 2014YZ0103 to De-Zhi Kang), major project of Fujian provincial department of science and technology (No. 2014YZ01 to DZK) and basic research and university production cooperation program of Fujian provincial department of science and technology, P.R.C. (No. 2018J01167 to PC).

Author information

LQS, CP, YLH, LYX, and KDZ conceived and designed the experiments and wrote the manuscript. LQS, CP, WWX, LCC, and ZSY performed and analyzed most experiments, including established PD model, neurobehavior tests, western blot, immunofluorescence staining, and qRT-PCR. ZY assisted in experiments. WWX performed preliminary experiments with no data used. XXF assisted in the design of the experiments. The study was supervised by KDZ.

Correspondence to De-Zhi Kang.

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