Axonal Degeneration Is Mediated by Necroptosis Activation
| Autor: | Felipe A. Court, Macarena S. Arrázola, Nicolas W. Martinez, Romina J. Catalán, Diego E. Hernandez, Cristian Saquel, Sebastian A. Barrientos, Alejandra Catenaccio |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Nervous system Dynamins Male Necroptosis Axonal loss Degeneration (medical) Biology Neuroprotection 03 medical and health sciences RIPK1 0302 clinical medicine medicine Animals Cells Cultured Research Articles General Neuroscience Neurodegeneration medicine.disease Sciatic Nerve Axons Mitochondria Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure nervous system Gene Knockdown Techniques Optic Nerve Injuries Receptor-Interacting Protein Serine-Threonine Kinases Nerve Degeneration Mitochondrial fission Female Wallerian Degeneration Neuroscience Protein Kinases 030217 neurology & neurosurgery |
| Zdroj: | The Journal of neuroscience : the official journal of the Society for Neuroscience. 39(20) |
| ISSN: | 1529-2401 |
| Popis: | 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 protectedin vitrosensory axons from degeneration after mechanical and toxic insults. These effects were also observed after genetic knock-down ofRIPK3, a second key regulator of necroptosis, and the downstream effectorMLKL(Mixed Lineage Kinase Domain-Like). RIPK1 inhibition prevented mitochondrial fragmentationin vitroandin 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.SIGNIFICANCE STATEMENTWe show that axonal degeneration triggered by diverse stimuli is mediated by the activation of the necroptotic programmed cell-death program by a cell-autonomous mechanism. This work represents a critical advance for the field since it identifies a defined degenerative pathway involved in axonal degeneration in both the peripheral nervous system and the CNS, a process that has been proposed as an early event in several neurodegenerative conditions and a major contributor to neuronal death. The identification of necroptosis as a key mechanism for axonal degeneration is an important step toward the development of novel therapeutic strategies for nervous-system disorders, particularly those related to chemotherapy-induced peripheral neuropathies or CNS diseases in which axonal degeneration is a common factor. |
| Databáze: | OpenAIRE |
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