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Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2024

Open Access 01-12-2024 | Research article

Microglial ferroptotic stress causes non-cell autonomous neuronal death

Authors: Jeffrey R. Liddell, James B. W. Hilton, Kai Kysenius, Jessica L. Billings, Sara Nikseresht, Lachlan E. McInnes, Dominic J. Hare, Bence Paul, Stephen W. Mercer, Abdel A. Belaidi, Scott Ayton, Blaine R. Roberts, Joseph S. Beckman, Catriona A. McLean, Anthony R. White, Paul S. Donnelly, Ashley I. Bush, Peter J. Crouch

Published in: Molecular Neurodegeneration | Issue 1/2024

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Abstract

Background

Ferroptosis is a form of regulated cell death characterised by lipid peroxidation as the terminal endpoint and a requirement for iron. Although it protects against cancer and infection, ferroptosis is also implicated in causing neuronal death in degenerative diseases of the central nervous system (CNS). The precise role for ferroptosis in causing neuronal death is yet to be fully resolved.

Methods

To elucidate the role of ferroptosis in neuronal death we utilised co-culture and conditioned medium transfer experiments involving microglia, astrocytes and neurones. We ratified clinical significance of our cell culture findings via assessment of human CNS tissue from cases of the fatal, paralysing neurodegenerative condition of amyotrophic lateral sclerosis (ALS). We utilised the SOD1G37R mouse model of ALS and a CNS-permeant ferroptosis inhibitor to verify pharmacological significance in vivo.

Results

We found that sublethal ferroptotic stress selectively affecting microglia triggers an inflammatory cascade that results in non-cell autonomous neuronal death. Central to this cascade is the conversion of astrocytes to a neurotoxic state. We show that spinal cord tissue from human cases of ALS exhibits a signature of ferroptosis that encompasses atomic, molecular and biochemical features. Further, we show the molecular correlation between ferroptosis and neurotoxic astrocytes evident in human ALS-affected spinal cord is recapitulated in the SOD1G37R mouse model where treatment with a CNS-permeant ferroptosis inhibitor, CuII(atsm), ameliorated these markers and was neuroprotective.

Conclusions

By showing that microglia responding to sublethal ferroptotic stress culminates in non-cell autonomous neuronal death, our results implicate microglial ferroptotic stress as a rectifiable cause of neuronal death in neurodegenerative disease. As ferroptosis is currently primarily regarded as an intrinsic cell death phenomenon, these results introduce an entirely new pathophysiological role for ferroptosis in disease.

Graphical Abstract

Appendix
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Metadata
Title
Microglial ferroptotic stress causes non-cell autonomous neuronal death
Authors
Jeffrey R. Liddell
James B. W. Hilton
Kai Kysenius
Jessica L. Billings
Sara Nikseresht
Lachlan E. McInnes
Dominic J. Hare
Bence Paul
Stephen W. Mercer
Abdel A. Belaidi
Scott Ayton
Blaine R. Roberts
Joseph S. Beckman
Catriona A. McLean
Anthony R. White
Paul S. Donnelly
Ashley I. Bush
Peter J. Crouch
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2024
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-023-00691-8

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