Microglial ferroptotic stress causes non-cell autonomous neuronal death.
Liddell, JR
Hilton, JBW
Kysenius, K
Billings, JL
Nikseresht, S
McInnes, LE
Hare, DJ
Paul, B
Mercer, SW
Belaidi, AA
Ayton, S
Roberts, BR
Beckman, JS
McLean, CA
White, AR
Donnelly, PS
Bush, AI
Crouch, PJ
- Publisher:
- Springer Nature
- Publication Type:
- Journal Article
- Citation:
- Mol Neurodegener, 2024, 19, (1), pp. 14
- Issue Date:
- 2024-02-05
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Full metadata record
Field | Value | Language |
---|---|---|
dc.contributor.author | Liddell, JR | |
dc.contributor.author | Hilton, JBW | |
dc.contributor.author | Kysenius, K | |
dc.contributor.author | Billings, JL | |
dc.contributor.author | Nikseresht, S | |
dc.contributor.author | McInnes, LE | |
dc.contributor.author | Hare, DJ | |
dc.contributor.author | Paul, B | |
dc.contributor.author | Mercer, SW | |
dc.contributor.author | Belaidi, AA | |
dc.contributor.author | Ayton, S | |
dc.contributor.author | Roberts, BR | |
dc.contributor.author | Beckman, JS | |
dc.contributor.author | McLean, CA | |
dc.contributor.author | White, AR | |
dc.contributor.author | Donnelly, PS | |
dc.contributor.author | Bush, AI | |
dc.contributor.author | Crouch, PJ | |
dc.date.accessioned | 2024-08-01T03:34:34Z | |
dc.date.available | 2023-11-28 | |
dc.date.available | 2024-08-01T03:34:34Z | |
dc.date.issued | 2024-02-05 | |
dc.identifier.citation | Mol Neurodegener, 2024, 19, (1), pp. 14 | |
dc.identifier.issn | 1750-1326 | |
dc.identifier.issn | 1750-1326 | |
dc.identifier.uri | http://hdl.handle.net/10453/179907 | |
dc.description.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. | |
dc.format | Electronic | |
dc.language | eng | |
dc.publisher | Springer Nature | |
dc.relation.ispartof | Mol Neurodegener | |
dc.relation.isbasedon | 10.1186/s13024-023-00691-8 | |
dc.rights | info:eu-repo/semantics/openAccess | |
dc.subject | 0604 Genetics, 1103 Clinical Sciences, 1109 Neurosciences | |
dc.subject.classification | Neurology & Neurosurgery | |
dc.subject.classification | 3101 Biochemistry and cell biology | |
dc.subject.classification | 3209 Neurosciences | |
dc.subject.mesh | Mice | |
dc.subject.mesh | Animals | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Microglia | |
dc.subject.mesh | Amyotrophic Lateral Sclerosis | |
dc.subject.mesh | Superoxide Dismutase-1 | |
dc.subject.mesh | Neurodegenerative Diseases | |
dc.subject.mesh | Cell Death | |
dc.subject.mesh | Disease Models, Animal | |
dc.subject.mesh | Microglia | |
dc.subject.mesh | Animals | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Mice | |
dc.subject.mesh | Amyotrophic Lateral Sclerosis | |
dc.subject.mesh | Neurodegenerative Diseases | |
dc.subject.mesh | Disease Models, Animal | |
dc.subject.mesh | Cell Death | |
dc.subject.mesh | Superoxide Dismutase-1 | |
dc.subject.mesh | Mice | |
dc.subject.mesh | Animals | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Microglia | |
dc.subject.mesh | Amyotrophic Lateral Sclerosis | |
dc.subject.mesh | Superoxide Dismutase-1 | |
dc.subject.mesh | Neurodegenerative Diseases | |
dc.subject.mesh | Cell Death | |
dc.subject.mesh | Disease Models, Animal | |
dc.title | Microglial ferroptotic stress causes non-cell autonomous neuronal death. | |
dc.type | Journal Article | |
utslib.citation.volume | 19 | |
utslib.location.activity | England | |
utslib.for | 0604 Genetics | |
utslib.for | 1103 Clinical Sciences | |
utslib.for | 1109 Neurosciences | |
pubs.organisational-group | University of Technology Sydney | |
pubs.organisational-group | University of Technology Sydney/Faculty of Science | |
pubs.organisational-group | University of Technology Sydney/Faculty of Science/School of Mathematical and Physical Sciences | |
utslib.copyright.status | open_access | * |
dc.rights.license | This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/ | |
dc.date.updated | 2024-08-01T03:34:27Z | |
pubs.issue | 1 | |
pubs.publication-status | Published online | |
pubs.volume | 19 | |
utslib.citation.issue | 1 |
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.
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