The necroptosis machinery mediates axonal degeneration in a model of Parkinson disease

  • A Correction to this article was published on 05 February 2020

Abstract

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.

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Change history

  • 05 February 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Acknowledgements

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).

Authors Contributions:

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.

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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

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