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Modeling Neuronal Death and Degeneration in Mouse Primary Cerebellar Granule Neurons
Published on: November 6, 2017
Microglial ferroptotic stress causes non-cell autonomous neuronal death
Jeffrey R Liddell1, James B W Hilton2, Kai Kysenius2
1Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC, 3010, Australia. jliddell@unimelb.edu.au.
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.
Insights
Microglial ferroptosis triggers inflammation, causing non-cell autonomous neuronal death in neurodegenerative diseases like ALS. Targeting ferroptosis offers a new therapeutic strategy for these conditions.
Area of Science:
- Neuroscience
- Cell Biology
- Pathology
Background:
- Ferroptosis, a regulated cell death marked by lipid peroxidation and iron dependence, plays a dual role in disease, contributing to neuronal death in neurodegenerative conditions.
- While ferroptosis is known to protect against cancer and infection, its precise role in central nervous system (CNS) neurodegeneration remains unclear.
Purpose of the Study:
- To investigate the role of ferroptosis in neuronal death within the context of neurodegenerative diseases.
- To elucidate the mechanisms by which ferroptosis influences neuronal survival and to explore potential therapeutic interventions.
Main Methods:
- Utilized co-culture systems with microglia, astrocytes, and neurons, alongside conditioned medium transfer experiments.
- Assessed human amyotrophic lateral sclerosis (ALS) spinal cord tissue and employed the SOD1G37R mouse model of ALS.
- Administered a CNS-permeant ferroptosis inhibitor (CuII(atsm)) in vivo to evaluate its therapeutic potential.
Main Results:
- Sublethal ferroptotic stress in microglia induced an inflammatory cascade leading to non-cell autonomous neuronal death.
- Astrocytes were converted to a neurotoxic state, contributing to the observed neuronal death.
- Human ALS spinal cord tissue exhibited a ferroptosis signature, which was mirrored in the SOD1G37R mouse model; treatment with CuII(atsm) ameliorated these markers and demonstrated neuroprotection.
Conclusions:
- Microglial ferroptotic stress is implicated as a key factor in non-cell autonomous neuronal death, suggesting it as a targetable cause of neuronal loss in neurodegenerative diseases.
- These findings reveal a novel pathophysiological role for ferroptosis beyond its traditional view as an intrinsic cell death mechanism, opening new avenues for therapeutic development in neurodegeneration.
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