Parkinson’s disease (PD) is the second most common neurodegenerative condition, characterized by motor impairment due to the progressive degeneration of dopaminergic neurons in the substantia nigra and depletion of dopamine release in the striatum. Accumulating evidence suggest that degeneration of axons is an early event in the disease, involving destruction programs that are independent of the survival of the cell soma. Necroptosis, a programmed cell death process, is emerging as a mediator of neuronal loss in models of neurodegenerative diseases. Here, we demonstrate activation of necroptosis in postmortem brain tissue from PD patients and in a toxin-based mouse model of the disease. Inhibition of key components of the necroptotic pathway resulted in a significant delay of 6-hydroxydopamine-dependent axonal degeneration of dopaminergic and cortical neurons in vitro. Genetic ablation of necroptosis mediators MLKL and RIPK3, as well as pharmacological inhibition of RIPK1 in preclinical models of PD, decreased dopaminergic neuron degeneration, improving motor performance. Together, these findings suggest that axonal degeneration in PD is mediated by the necroptosis machinery, a process here referred to as necroaxoptosis, a druggable pathway to target dopaminergic neuronal loss.
Subscribe to Journal
Get full journal access for 1 year
only $42.79 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Lau L, Breteler M. Epidemiology of Parkinson’s disease. Neurol Rev. 2006;5:525–35.
Goldman JG, Postuma R. Premotor and nonmotor features of Parkinson’s disease. Curr Opin Neurol. 2014;27:434–41.
Dauer W, Przedborski S. Parkinson’s disease: mechanisms and models. Neuron. 2003;39:889–909.
Corti O, Lesage S, Brice A. What genetics tells us about the causes and mechanisms of Parkinson’s disease. Physiol Rev. 2011;91:1161–218.
Tagliaferro P, Burke RE. Retrograde axonal degeneration in Parkinson disease. J Park Dis. 2016;6:1–15.
Kramer ML, Schulz-Schaeffer WJ. Presynaptic alpha-synuclein aggregates, not Lewy bodies, cause neurodegeneration in dementia with Lewy bodies. J Neurosci. 2007;27:1405–10.
Kordower JH, Olanow CW, Dodiya HB, Chu Y, Beach TG, Adler CH, et al. Disease duration and the integrity of the nigrostriatal system in Parkinson’s disease. Brain. 2013;136:2419–31.
Orimo S, Uchihara T, Nakamura A, Mori F, Kakita A, Wakabayashi K, et al. Axonal alpha-synuclein aggregates herald centripetal degeneration of cardiac sympathetic nerve in Parkinson’s disease. Brain. 2008;131:642–50.
Li Y, Liu W, Oo TF, Wang L, Tang Y, Jackson-Lewis V, et al. Mutant LRRK2(R1441G) BAC transgenic mice recapitulate cardinal features of Parkinson’s disease. Nat Neurosci. 2009;12:826–8.
von Coelln R, Kugler S, Bahr M, Weller M, Dichgans J, Schulz JB. Rescue from death but not from functional impairment: caspase inhibition protects dopaminergic cells against 6-hydroxydopamine-induced apoptosis but not against the loss of their terminals. J Neurochem. 2001;77:263–73.
Eberhardt O, Coelln RV, Ku S, Rathke-hartlieb S, Gerhardt E, Haid S, et al. Protection by synergistic effects of adenovirus-mediated X-chromosome-linked inhibitor of apoptosis and glial cell line-derived neurotrophic factor gene transfer in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. J Neurosci. 2000;20:9126–34.
Ries V, Silva RM, Oo TF, Cheng H-C, Rzhetskaya M, Kholodilov N, et al. JNK2 and JNK3 combined are essential for apoptosis in dopamine neurons of the substantia nigra, but are not required for axon degeneration. J Neurochem. 2008;107:1578–88.
Salvadores N, Sanhueza M, Manque P, Court FA. Axonal degeneration during aging and its functional role in neurodegenerative disorders. Front Neurosci. 2017;11:https://doi.org/10.3389/fnins.2017.00451.
Court FA, Coleman MP. Mitochondria as a central sensor for axonal degenerative stimuli. Trends Neurosci. 2012;35:364–72.
Hernandez DE, Salvadores NA, Moya-alvarado G, Catalna RJ, Bronfman FC, Court FA. Axonal degeneration induced by glutamate excitotoxicity is mediated by necroptosis. J Cell Sci. 2018;131:https://doi.org/10.1242/jcs.214684.
Arrazola MS, Saquel C, Catalan RJ, Barrientos SA, Hernandez DE, Martinez NW, et al. Axonal degeneration is mediated by necroptosis activation. J Neurosci. 2019;39:3832–44.
Shan B, Pan H, Najafov A, Yuan J. Necroptosis in development and diseases. Genes Dev. 2003;32:327–40.
Tonnus W, Linkermann A. The in vivo evidence for regulated necrosis. Immunol Rev. 2017;277:128–49.
Wallach D, Kang T-B, Dillon CP, Green DR. Programmed necrosis in inflammation: toward identification of the effector molecules. Science. 2016;352:aaf2154.
Grootjans S, Vanden Berghe T, Vandenabeele P. Initiation and execution mechanisms of necroptosis: an overview. Cell Death Differ. 2017;24:1184–95.
Weinlich R, Oberst A, Beere HM, Green DR. Necroptosis in development, inflammation and disease. Nat Rev Mol Cell Biol. 2017;18:127–36.
Bertrand MJM, Milutinovic S, Dickson KM, Ho WC, Boudreault A, Durkin J, et al. cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. Mol Cell. 2008;30:689–700.
Kondylis V, Kumari S, Vlantis K, Pasparakis M. The interplay of IKK, NF-κB and RIPK1 signaling in the regulation of cell death, tissue homeostasis and inflammation. Immunol Rev. 2017;277:113–27.
Petrie EJ, Czabotar PE, Murphy JM. The structural basis of necroptotic cell death signaling. Trends Biochem Sci. 2019;44:53–63.
Sun L, Wang H, Wang Z, He S, Chen S, Liao D, et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell. 2012;148:213–27.
Gong YN, Guy C, Crawford JC, Green DR. Biological events and molecular signaling following MLKL activation during necroptosis. Cell Cycle. 2017;16:1748–60.
Cai Z, Jitkaew S, Zhao J, Chiang HC, Choksi S, Liu J, et al. Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis. Nat Cell Biol. 2014;16:55–65.
Yang Z, Wang Y, Zhang Y, He X, Zhong CQ, Ni H, et al. RIP3 targets pyruvate dehydrogenase complex to increase aerobic respiration in TNF-induced necroptosis. Nat Cell Biol. 2018;20:186–97.
Yuan J, Amin P, Ofengeim D. Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases. Nat Rev Neurosci. 2019;20:19–33.
Qu Y, Shi J, Tang Y, Zhao F, Li S, Meng J, et al. MLKL inhibition attenuates hypoxia-ischemia induced neuronal damage in developing brain. Exp Neurol. 2016;279:223–31.
Yin B, Xu Y, Wei RL, He F, Luo BY, Wang JY. Inhibition of receptor-interacting protein 3 upregulation and nuclear translocation involved in Necrostatin-1 protection against hippocampal neuronal programmed necrosis induced by ischemia/reperfusion injury. Brain Res. 2015;1609:63–71.
Zhang S, Wang Y, Li D, Wu J, Si W, Wu Y. Necrostatin-1 attenuates inflammatory response and improves cognitive function in chronic ischemic stroke mice. Medicines. 2016;3:16.
You Z, Savitz SI, Yang J, Degterev A, Yuan J, Cuny GD, et al. Necrostatin-1 reduces histopathology and improves functional outcome after controlled cortical impact in mice. J Cereb Blood Flow Metab. 2008;28:1564–73.
Bian P, Zheng X, Wei L, Ye C, Fan H, Cai Y, et al. MLKL mediated necroptosis accelerates JEV-induced neuroinflammation in mice. Front Microbiol 2017;8:1–10.
Dong K, Zhu H, Song Z, Gong Y, Wang F, Wang W, et al. Necrostatin-1 protects photoreceptors from cell death and improves functional outcome after experimental retinal detachment. Am J Pathol. 2012;181:1634–41.
Kim CR, Kim JH, Park HYL, Park CK. Ischemia reperfusion injury triggers TNFα induced-necroptosis in rat retina. Curr Eye Res. 2016;42:771–9.
Viringipurampeer IA, Shan X, Gregory-Evans K, Zhang JP, Mohammadi Z, Gregory-Evans CY. Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish. Cell Death Differ. 2014;21:665–75.
Liu M, Wu W, Li H, Li S, Huang LT, Yang YQ, et al. Necroptosis, a novel type of programmed cell death, contributes to early neural cells damage after spinal cord injury in adult mice. J Spinal Cord Med. 2015;38:745–53.
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.
Re DB, Le Verche V, Yu C, Amoroso MW, Politi KA, Phani S, et al. Necroptosis drives motor neuron death in models of both sporadic and familial ALS. Neuron. 2014;81:1001–8.
Ofengeim D, Ito Y, Najafov A, Zhang Y, Shan B, DeWitt JP, et al. Activation of necroptosis in multiple sclerosis. Cell Rep. 2015;10:1836–49.
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.
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.
Wu JR, Wang J, Zhou SK, Yang L, Le YinJ, Cao JP, et al. Necrostatin-1 protection of dopaminergic neurons. Neural Regen Res. 2015;10:1120–4.
Takahashi N, Duprez L, Grootjans S, Cauwels A, Nerinckx W, Duhadaway JB, et al. Necrostatin-1 analogues: critical issues on the specificity, activity and in vivo use in experimental disease models. Cell Death Dis. 2012;3:e437–10.
Declercq W, Vanden Berghe T, Vandenabeele P. RIP kinases at the crossroads of cell death and survival. Cell. 2009;138:229–32.
Hildebrand JM, Tanzer MC, Lucet IS, Young SN, Spall SK, Sharma P, et al. Activation of the pseudokinase MLKL unleashes the four-helix bundle domain to induce membrane localization and necroptotic cell death. Proc Natl Acad Sci USA. 2014;111:15072–7.
Braak H, Rüb U, Gai WP, Tredici K Del. Idiopathic Parkinson’ s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm (Vienna). 2003;110:517–36.
Zhang J, Yang Y, He W, Sun L. Necrosome core machinery: MLKL. Cell Mol Life Sci. 2016;73:2153–63.
Cheng HC, Ulane CM, Burke RE. Clinical progression in Parkinson disease and the neurobiology of axons. Ann Neurol. 2010;67:715–25.
Chung CY, Koprich JB, Siddiqi H, Isacson O. Dynamic changes in presynaptic and axonal transport proteins combined with striatal neuroinflammation precede dopaminergic neuronal loss in a rat model of AAV-synucleinopathy. J Neurosci. 2009;29:3365–73.
Tagliaferro P, Kareva T, Oo TF, Yarygina O, Kholodilov N, Burke RE. An early axonopathy in a hLRRK2(R1441G) transgenic model of Parkinson disease. Neurobiol Dis. 2015;82:359–71.
Matsuda W, Furuta T, Nakamura KC, Hioki H, Fujiyama F, Arai R, et al. Single nigrostriatal dopaminergic neurons form widely spread and highly dense axonal arborizations in the neostriatum. J Neurosci. 2009;29:444–53.
West MJ. Estimating length in biological structures. Cold Spring Harb Protoc. 2013;8:412–20.
Shao L, Yu S, Ji W, Li H, Gao Y. The contribution of necroptosis in neurodegenerative diseases. Neurochem Res. 2017;42:2117–26.
Zhang S, Tang M, Luo H, Shi C, Xu Y. Necroptosis in neurodegenerative diseases: a potential therapeutic target. Cell Death Dis. 2017;8:e2905.
Collins LM, Toulouse A, Connor TJ, Nolan YM. Contributions of central and systemic inflammation to the pathophysiology of Parkinson’s disease. Neuropharmacology. 2012;62:2153–67.
Croisier E, Moran LB, Dexter DT, Pearce RKB, Graeber MB. Microglial inflammation in the parkinsonian substantia nigra: relationship to alpha-synuclein deposition. J Neuroinflamm. 2005;2:1–8.
Ferger B, Leng A, Mura A, Hengerer B, Feldon J. Genetic ablation of tumor necrosis factor-alpha (TNF-α) and pharmacological inhibition of TNF-synthesis attenuates MPTP toxicity in mouse striatum. J Neurochem. 2004;89:822–33.
Wegner KW, Saleh D, Degterev A. Complex pathologic roles of RIPK1 and RIPK3: moving beyond necroptosis. Trends Pharm Sci. 2017;38:202–25.
Hsu LJ, Sagara Y, Arroyo A, Rockenstein E, Sisk A, Mallory M, et al. Alpha-synuclein promotes mitochondrial deficit and oxidative. Stress. 2000;157:401–10.
Ko L, Mehta ND, Farrer M, Easson C, Hussey J, Yen S, et al. Sensitization of neuronal cells to oxidative stress with mutated human alpha-synuclein. J Neurochem. 2000;75:2546–56.
Orth M, Tabrizi SJ, Tomlinson C, Messmer K, Korlipara LVP, Schapira AHV, et al. G209A mutant alpha synuclein expression specifically enhances dopamine induced oxidative damage. Neurochemistry. 2004;45:669–76.
Surmeier DJ, Guzman JN, Sanchez-padilla J, Goldberg JA. The origins of oxidant stress in Parkinson’s disease and therapeutic strategies. Antioxid Redox Signal. 2011;14:1289–301.
Dillon CP, Weinlich R, Rodriguez DA, Cripps JG, Quarato G, Gurung P, et al. RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3. Cell. 2014;157:1189–202.
Oberst A, Dillon CP, Weinlich R, McCormick LL, Fitzgerald P, Pop C, et al. Catalytic activity of the caspase-8–FLIPL complex inhibits RIPK3-dependent necrosis. Nature. 2011;471:363–7.
Murphy JM, Czabotar PE, Hildebrand JM, Lucet IS, Zhang JG, Alvarez-Diaz S, et al. The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism. Immunity. 2013;39:443–53.
Newton K, Sun X, Dixit VM. Kinase RIP3 is dispensable for normal NF-kappa Bs, signaling by the B-cell and T-cell receptors, tumor necrosis factor receptor 1, and Toll-like receptors 2 and 4. Mol Cell Biol. 2004;24:1464–9.
Paxinos G, Franklin K. The mouse brain in stereotaxic coordinates. 3rd ed. p. 256. Amsterdam: Academic Press. 2008.
Castillo V, Oñate M, Woehlbier U, Rozas P, Andreu C, Medinas D, et al. Functional role of the disulfide isomerase ERp57 in axonal regeneration. PLoS ONE. 2015;10:e0136620.
We are grateful to the Banner Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona for the provision of brain tissue. This work was supported by Geroscience Center for Brain Health and Metabolism FONDAP-15150012 (FAC and CH), Ring Initiative ACT1109 (FAC and CH), FONDECYT-1150766 and FONDECYT-1190518, Canada-Israel Health Research initiative, jointly Funded by the Canadian Institutes of Health Research, the Israel Science Foundation, the international Development Research Centre, Canada and the Azrieli Foundation, Canada (FAC), Conicyt Doctoral Fellowship 21130843 (MO), FONDECYT 1140549 (CH), Millennium Institute P09-015-F (CH), European Commission R&D MSCA-RISE 734749 (CH). Michael J Fox Foundation for Parkinson's Research—Target Validation grant 9277 (CH), FONDEF ID16I10223 (CH), FONDEF D11E1007 (CH), US Office of Naval Research-Global N62909-16-1-2003 (CH), U.S. Air Force Office of Scientific Research FA9550-16-1-0384 (CH), ALSRP Therapeutic Idea Award AL150111 (CH), Muscular Dystrophy Association 382453 (CH), and CONICYT-Brazil 441921/2016-7 (CH).
MO, AC, NS, CS*, IM-G, NG, and PS performed the experiments MO, AC, CS*, AM, and NG analyzed the data. MO, IM-G, CS**, CH, and FAC designed experiments and wrote the manuscript. *Cristian Saquel and **Claudio Soto.
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Edited by M. Deshmukh
About this article
Cite this article
Oñate, M., Catenaccio, A., Salvadores, N. et al. The necroptosis machinery mediates axonal degeneration in a model of Parkinson disease. Cell Death Differ 27, 1169–1185 (2020). https://doi.org/10.1038/s41418-019-0408-4
Cobalt nanoparticles trigger ferroptosis-like cell death (oxytosis) in neuronal cells: Potential implications for neurodegenerative disease
The FASEB Journal (2020)
The necroptosis pathway and its role in age-related neurodegenerative diseases: will it open up new therapeutic avenues in the next decade?
Expert Opinion on Therapeutic Targets (2020)
Molecular Insights into the Mechanism of Necroptosis: The Necrosome as a Potential Therapeutic Target