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Axonal degeneration is mediated by necroptosis activation

Arrázola, Macarena S. ; Saquel, Cristian ; Catalán, Romina J. ; Barrientos, Sebastián A. LU ; Hernandez, Diego E. ; Martínez, Nicolás W. ; Catenaccio, Alejandra and Court, Felipe A. (2019) In Journal of Neuroscience 39(20). p.3832-3844
Abstract

Axonal degeneration, which contributes to functional impairment in several disorders of the nervous system, is an important target for neuroprotection. Several individual factors and subcellular events have been implicated in axonal degeneration, but researchers have so far been unable to identify an integrative signaling pathway activating this self-destructive process. Through pharmacological and genetic approaches, we tested whether necroptosis, a regulated cell-death mechanism implicated in the pathogenesis of several neurodegenerative diseases, is involved in axonal degeneration. Pharmacological inhibition of the necroptotic kinase RIPK1 using necrostatin-1 strongly delayed axonal degeneration in the peripheral nervous system and... (More)

Axonal degeneration, which contributes to functional impairment in several disorders of the nervous system, is an important target for neuroprotection. Several individual factors and subcellular events have been implicated in axonal degeneration, but researchers have so far been unable to identify an integrative signaling pathway activating this self-destructive process. Through pharmacological and genetic approaches, we tested whether necroptosis, a regulated cell-death mechanism implicated in the pathogenesis of several neurodegenerative diseases, is involved in axonal degeneration. Pharmacological inhibition of the necroptotic kinase RIPK1 using necrostatin-1 strongly delayed axonal degeneration in the peripheral nervous system and CNS of wild-type mice of either sex and protected in vitro sensory axons from degeneration after mechanical and toxic insults. These effects were also observed after genetic knock-down of RIPK3, a second key regulator of necroptosis, and the downstream effector MLKL (Mixed Lineage Kinase Domain-Like). RIPK1 inhibition prevented mitochondrial fragmentation in vitro and in vivo, a typical feature of necrotic death, and inhibition of mitochondrial fission by Mdivi also resulted in reduced axonal loss in damaged nerves. Furthermore, electrophysiological analysis demonstrated that inhibition of necroptosis delays not only the morphological degeneration of axons, but also the loss of their electrophysiological function after nerve injury. Activation of the necroptotic pathway early during injury-induced axonal degeneration was made evident by increased phosphorylation of the downstream effector MLKL. Our results demonstrate that axonal degeneration proceeds by necroptosis, thus defining a novel mechanistic framework in the axonal degenerative cascade for therapeutic interventions in a wide variety of conditions that lead to neuronal loss and functional impairment.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Axonal degeneration, Mitochondrial fragmentation, MLKL, Necroptosis, Neurodegeneration, RIP kinase
in
Journal of Neuroscience
volume
39
issue
20
pages
13 pages
publisher
Society for Neuroscience
external identifiers
  • scopus:85066826437
  • pmid:30850513
ISSN
0270-6474
DOI
10.1523/JNEUROSCI.0881-18.2019
language
English
LU publication?
yes
id
54c85492-8ddc-4bb8-b145-aaca0b83926d
date added to LUP
2019-07-03 13:08:17
date last changed
2020-03-24 06:58:01
@article{54c85492-8ddc-4bb8-b145-aaca0b83926d,
  abstract     = {<p>Axonal degeneration, which contributes to functional impairment in several disorders of the nervous system, is an important target for neuroprotection. Several individual factors and subcellular events have been implicated in axonal degeneration, but researchers have so far been unable to identify an integrative signaling pathway activating this self-destructive process. Through pharmacological and genetic approaches, we tested whether necroptosis, a regulated cell-death mechanism implicated in the pathogenesis of several neurodegenerative diseases, is involved in axonal degeneration. Pharmacological inhibition of the necroptotic kinase RIPK1 using necrostatin-1 strongly delayed axonal degeneration in the peripheral nervous system and CNS of wild-type mice of either sex and protected in vitro sensory axons from degeneration after mechanical and toxic insults. These effects were also observed after genetic knock-down of RIPK3, a second key regulator of necroptosis, and the downstream effector MLKL (Mixed Lineage Kinase Domain-Like). RIPK1 inhibition prevented mitochondrial fragmentation in vitro and in vivo, a typical feature of necrotic death, and inhibition of mitochondrial fission by Mdivi also resulted in reduced axonal loss in damaged nerves. Furthermore, electrophysiological analysis demonstrated that inhibition of necroptosis delays not only the morphological degeneration of axons, but also the loss of their electrophysiological function after nerve injury. Activation of the necroptotic pathway early during injury-induced axonal degeneration was made evident by increased phosphorylation of the downstream effector MLKL. Our results demonstrate that axonal degeneration proceeds by necroptosis, thus defining a novel mechanistic framework in the axonal degenerative cascade for therapeutic interventions in a wide variety of conditions that lead to neuronal loss and functional impairment.</p>},
  author       = {Arrázola, Macarena S. and Saquel, Cristian and Catalán, Romina J. and Barrientos, Sebastián A. and Hernandez, Diego E. and Martínez, Nicolás W. and Catenaccio, Alejandra and Court, Felipe A.},
  issn         = {0270-6474},
  language     = {eng},
  number       = {20},
  pages        = {3832--3844},
  publisher    = {Society for Neuroscience},
  series       = {Journal of Neuroscience},
  title        = {Axonal degeneration is mediated by necroptosis activation},
  url          = {http://dx.doi.org/10.1523/JNEUROSCI.0881-18.2019},
  doi          = {10.1523/JNEUROSCI.0881-18.2019},
  volume       = {39},
  year         = {2019},
}