Year: 2024
Type: article
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 SOD1 G37R 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 SOD1 G37R mouse model where treatment with a CNS-permeant ferroptosis inhibitor, Cu II (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
Source: Molecular Neurodegeneration
Authors: Jeffrey R. Liddell, James B.W. Hilton, Kai Kysenius, Sara Nikseresht, Lachlan E. McInnes, Dominic J. Hare, Bence Paul, Benjamin G. Trist, Kay L. Double, Stephen W. Mercer, Scott Ayton, Blaine R. Roberts, Joseph S. Beckman, Catriona A. McLean, Anthony R. White, Paul S. Donnelly, Ashley I. Bush, Peter J. Crouch
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,990
Funders: FightMND, Motor Neurone Disease Australia, Motor Neurone Disease Research Australia, Imperial College London, King's College London, University of Melbourne, Università degli Studi di Padova, National Institutes of Health, Medical Research Council, Menzies Centre for Australian Studies, King's College London, University of London, National Health and Medical Research Council
Awards: Metal complexes for the treatment of age-related diseases of the brain, Impaired mitochondrial energy metabolism and the therapeutic activity of Cu(atsm) in age and age-related neurodegenerative disease, Harnessing the consequences of impaired mitochondrial function to treat and image motor neuron disease, Superoxide dismutase one dysfunction: a novel pathogenic mechanism in Parkinson disease
OpenAlex ID: W4391539554