4.7 Article

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

Journal

CELL DEATH AND DIFFERENTIATION
Volume 27, Issue 4, Pages 1169-1185

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/s41418-019-0408-4

Keywords

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Funding

  1. Geroscience Center for Brain Health and Metabolism [FONDAP15150012]
  2. Ring Initiative [ACT1109]
  3. FONDECYT [1140549]
  4. Canada-Israel Health Research initiative - Canadian Institutes of Health Research
  5. Israel Science Foundation
  6. international Development Research Centre, Canada
  7. Azrieli Foundation, Canada
  8. Conicyt [21130843]
  9. Millennium Institute [P09-015-F]
  10. European Commission RD [MSCA-RISE 734749]
  11. Michael J Fox Foundation for Parkinson's Research-Target Validation grant [9277]
  12. FONDEF [ID16I10223, D11E1007]
  13. US Office of Naval Research-Global [N62909-16-1-2003]
  14. U.S. Air Force Office of Scientific Research [FA9550-16-1-0384]
  15. ALSRP Therapeutic Idea Award [AL150111]
  16. Muscular Dystrophy Association [382453]
  17. CONICYT-Brazil [441921/2016-7]
  18. [FONDECYT-1150766]
  19. [FONDECYT-1190518]

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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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