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

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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.

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References

  1. 1.

    de Lau LM, Breteler MM. Epidemiology of Parkinson’s disease. The Lancet Neurology. 2006;5:525–35.

  2. 2.

    Latourelle JC, Beste MT, Hadzi TC, Miller RE, Oppenheim JN, Valko MP, et al. Large-scale identification of clinical and genetic predictors of motor progression in patients with newly diagnosed Parkinson’s disease: a longitudinal cohort study and validation. Lancet Neurol. 2017;16:908–16.

  3. 3.

    Soldner F, Stelzer Y, Shivalila CS, Abraham BJ, Latourelle JC, Barrasa MI, et al. Parkinson-associated risk variant in distal enhancer of alpha-synuclein modulates target gene expression. Nature. 2016;533:95–9.

  4. 4.

    Zhao WZ, Wang HT, Huang HJ, Lo YL, Lin AM. Neuroprotective effects of baicalein on acrolein-induced neurotoxicity in the nigrostriatal dopaminergic system of rat brain. Mol Neurobiol. 2017;55:130–7.

  5. 5.

    Zhou Y, Lu M, Du R-H, Qiao C, Jiang C-Y, Zhang K-Z, et al. MicroRNA-7 targets nod-like receptor protein 3 inflammasome to modulate neuroinflammation in the pathogenesis of Parkinson’s disease. Mol Neurodegener. 2016;11. https://doi.org/10.1186/s13024-016-0094-3.

  6. 6.

    Xu Y, Ma H, Shao J, Wu J, Zhou L, Zhang Z, et al. A role for tubular necroptosis in cisplatin-induced AKI. J Am Soc Nephrol. 2015;26:2647–58.

  7. 7.

    Wallach D, Kang TB, Dillon CP, Green DR. Programmed necrosis in inflammation: toward identification of the effector molecules. Science. 2016;352:aaf2154.

  8. 8.

    Rickard JA, O’Donnell JA, Evans JM, Lalaoui N, Poh AR, Rogers T, et al. RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis. Cell. 2014;157:1175–88.

  9. 9.

    Zhang T, Zhang Y, Cui M, Jin L, Wang Y, Lv F, et al. CaMKII is a RIP3 substrate mediating ischemia- and oxidative stress-induced myocardial necroptosis. Nat Med. 2016;22:175–82.

  10. 10.

    Wang H, Sun L, Su L, Rizo J, Liu L, Wang LF, et al. Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol Cell. 2014;54:133–46.

  11. 11.

    Ito Y, Ofengeim D, Najafov A, Das S, Saberi S, Li Y, et al. RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS. Science. 2016;353:603–8.

  12. 12.

    Wang H, Ye Y, Zhu Z, Mo L, Lin C, Wang Q, et al. MiR-124 regulates apoptosis and autophagy process in MPTP model of Parkinson’s disease by targeting to bim. Brain Pathol. 2016;26:167–76.

  13. 13.

    Liu J, Liu W, Lu Y, Tian H, Duan C, Lu L, et al. Piperlongumine restores the balance of autophagy and apoptosis by increasing BCL2 phosphorylation in rotenone-induced Parkinson disease models. Autophagy. 2018;14:845–61.

  14. 14.

    Dionisio PEA, Oliveira SR, Amaral J, Rodrigues CMP. Loss of microglial Parkin inhibits necroptosis and contributes to neuroinflammation. Mol Neurobiol. 2018;56:2990–3004.

  15. 15.

    Iannielli A, Bido S, Folladori L, Segnali A, Cancellieri C, Maresca A, et al. Pharmacological inhibition of necroptosis protects from dopaminergic neuronal cell death in Parkinson’s disease models. Cell Rep. 2018;22:2066–79.

  16. 16.

    Jackson-Lewis V, Przedborski S. Protocol for the MPTP mouse model of Parkinson’s disease. Nat Protoc. 2007;2:141–51.

  17. 17.

    Peng S, Wang C, Ma J, Jiang K, Jiang Y, Gu X, et al. Achyranthes bidentata polypeptide protects dopaminergic neurons from apoptosis in Parkinson’s disease models both in vitro and in vivo. Br J Pharmacol. 2017;175:631–43.

  18. 18.

    Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol. 2005;1:112–9.

  19. 19.

    Hasegawa K, Yasuda T, Shiraishi C, Fujiwara K, Przedborski S, Mochizuki H, et al. Promotion of mitochondrial biogenesis by necdin protects neurons against mitochondrial insults. Nat Commun. 2016;7:10943.

  20. 20.

    Zhou K, Shi L, Wang Z, Zhou J, Manaenko A, Reis C, et al. RIP1-RIP3-DRP1 pathway regulates NLRP3 inflammasome activation following subarachnoid hemorrhage. Exp Neurol. 2017;295:116–24.

  21. 21.

    He S, Wang L, Miao L, Wang T, Du F, Zhao L, et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell. 2009;137:1100–11.

  22. 22.

    Zhang DW, Shao J, Lin J, Zhang N, Lu BJ, Lin SC, et al. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science. 2009;325:332–6.

  23. 23.

    Wu J, Huang Z, Ren J, Zhang Z, He P, Li Y, et al. Mlkl knockout mice demonstrate the indispensable role of Mlkl in necroptosis. Cell Res. 2013;23:994–1006.

  24. 24.

    Lalaoui N, Lindqvist LM, Sandow JJ, Ekert PG. The molecular relationships between apoptosis, autophagy and necroptosis. Semin Cell Dev Biol. 2015;39:63–9.

  25. 25.

    Daniels BP, Snyder AG, Olsen TM, Orozco S, Oguin TH 3rd, Tait SWG, et al. RIPK3 restricts viral pathogenesis via cell death-independent neuroinflammation. Cell. 2017;169:301–13 e11.

  26. 26.

    Sathe K, Maetzler W, Lang JD, Mounsey RB, Fleckenstein C, Martin HL, et al. S100B is increased in Parkinson’s disease and ablation protects against MPTP-induced toxicity through the RAGE and TNF-alpha pathway. Brain. 2012;135:3336–47.

  27. 27.

    Iravani MM, Sadeghian M, Leung CC, Jenner P, Rose S. Lipopolysaccharide-induced nigral inflammation leads to increased IL-1beta tissue content and expression of astrocytic glial cell line-derived neurotrophic factor. Neurosci Lett. 2012;510:138–42.

  28. 28.

    Caccamo A, Branca C, Piras IS, Ferreira E, Huentelman MJ, Liang WS, et al. Necroptosis activation in Alzheimer’s disease. Nat Neurosci. 2017;20:1236–46.

  29. 29.

    Niranjan R. The role of inflammatory and oxidative stress mechanisms in the pathogenesis of Parkinson’s disease: focus on astrocytes. Mol Neurobiol. 2014;49:28–38.

  30. 30.

    Newton K, Dugger DL, Wickliffe KE, Kapoor N, de Almagro MC, Vucic D, et al. Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis. Science. 2014;343:1357–60.

  31. 31.

    He S, Liang Y, Shao F, Wang X. Toll-like receptors activate programmed necrosis in macrophages through a receptor-interacting kinase-3-mediated pathway. PNAS. 2011;108:20054–9.

  32. 32.

    Selimkhanov J, Thompson WC, Guo J, Hall KD, Musante CJ. A quantitative analysis of statistical power identifies obesity end points for improved in vivo preclinical study design. Int J Obes. 2017;41:1306–9.

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Acknowledgements

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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