Axonal degeneration induced by glutamate-excitotoxicity is mediated by necroptosis

Hernandez, D. E., Salvadores, N. A., Moya-Alvarado, G., Catalan, R. J., Bronfman, F. C., Court, F. A. (October 2018) Axonal degeneration induced by glutamate-excitotoxicity is mediated by necroptosis. J Cell Sci, 131 (22). ISSN 0021-9533

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DOI: 10.1242/jcs.214684


Neuronal excitotoxicity induced by glutamate leads to cell death and functional impairment in a variety of central nervous system pathologies. Glutamate-mediated excitotoxicity triggers neuronal apoptosis in the cell soma as well as degeneration of axons and dendrites by a process associated to calcium increase and mitochondrial dysfunction. Importantly, degeneration of axons initiated by diverse stimuli, including excitotoxicity, has been proposed as an important pathological event leading to functional impairment in neurodegenerative conditions. Here we demonstrate that excitotoxicity-induced axonal degeneration proceeds by a mechanism dependent on the necroptotic kinases RIPK1, RIPK3 and the necroptotic mediator MLKL. Inhibition of RIPK1, RIPK3 or MLKL prevent key steps in the axonal degeneration cascade including mitochondrial depolarization, the opening of the permeability transition pore and calcium dysregulation in the axon. Interestingly, the same excitotoxic stimuli lead to apoptosis in the cell soma, demonstrating the co-activation of two independent degenerative mechanisms in different compartments of the same cell. The identification of necroptosis as a key mechanism of axonal degeneration after excitotoxicity is an important initial step to develop novel therapeutic strategies for nervous system disorders.

Item Type: Paper
Subjects: organs, tissues, organelles, cell types and functions > tissues types and functions > axon
bioinformatics > genomics and proteomics > small molecules > Glutamate
CSHL Authors:
Depositing User: Adrian Gomez
Date: 17 October 2018
Date Deposited: 09 Jan 2020 17:40
Last Modified: 09 Jan 2020 17:40
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