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J Cell Sci. 2018 Nov 19;131(22). pii: jcs214684. doi: 10.1242/jcs.214684.

Axonal degeneration induced by glutamate excitotoxicity is mediated by necroptosis.

Author information

1
Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile.
2
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
3
Center of Advanced Microscopy (CMA), Universidad de Concepción, Concepción 4070386, Chile.
4
FONDAP Center for Geroscience, Brain Health and Metabolism, Santiago 8580745, Chile.
5
Center for Ageing and Regeneration (CARE UC), Faculty of Biological Sciences, Department of Physiology, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile.
6
Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile felipe.court@umayor.cl.
7
Buck Institute for Research on Ageing, Novato, San Francisco, CA 94945, USA.

Abstract

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 with Ca2 + 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 and RIPK3, and the necroptotic mediator MLKL. Inhibition of RIPK1, RIPK3 or MLKL prevents key steps in the axonal degeneration cascade, including mitochondrial depolarization, the opening of the permeability transition pore and Ca2+ 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 in the development of novel therapeutic strategies for nervous system disorders.

KEYWORDS:

Axonal degeneration; Excitotoxicity; Necroptosis; Neurodegeneration

PMID:
30333135
DOI:
10.1242/jcs.214684
[Indexed for MEDLINE]
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