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. 2024 Feb 5;19:14. doi: 10.1186/s13024-023-00691-8

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© The Author(s) 2024, Corrected publication. February 2024

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

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Fig. 7 — Treatment with Cu^II(atsm) is protective and mitigates markers of ferroptosis and glial activation in ALS model mice. a Stage of phenotype progression in transgenic SOD1^G37R ALS model mice (ALS-Tg) at which treatment with Cu^II(atsm) commenced for the present study. Percentage starting body weight for SOD1^G37R mice is expressed relative to body weight per animal at 50 days old. Percentage motor function (rotarod assay) is expressed relative to average performance per animal over the period 125–139 days (n = 14–21 animals). b Effect of Cu^II(atsm) at 30 mg/kg body weight twice daily on motor function of SOD1^G37R mice. c Rate of motor function decline in SOD1^G37R mice derived from data in b. d Cu^II(atsm), administered orally commencing at the post symptom-onset age of 140 days, extends survival of the SOD1^G37R mouse model of ALS. e-h Therapeutic outcomes for Cu^II(atsm) in the SOD1^G37R mice are associated with improved biochemical markers of ferroptosis, including decreased iron levels, increased ferroxidase activity, decreased lipid peroxidation and increased GPX4 protein in extracted spinal cord tissue. Lipid peroxidation in g measured as oxidised:reduced C11-BODIPY. i Volcano plot of transcript analyses for genes associated with ferroptosis and neurotoxic glial activation in SOD1^G37R mouse spinal cord tissue treated with Cu^II(atsm) compared to SOD1^G37R mice without Cu^II(atsm) treatment. j Overall transcript signature for ferroptosis and neurotoxic glial genes are mitigated by Cu^II(atsm) treatment, including genes associated with neurotoxicity in vitro (Neurotoxic), derived from i and Fig. 5g-j. k Correlation between overall transcript signatures for ferroptosis and neurotoxic glia (from j and Fig. 5h, j). Symbols represent individual animals. In e-h, j, data points represent individual SOD1^G37R mice treated with Cu^II(atsm); purple solid lines and grey dashed lines and represent mean of SOD1^G37R without Cu^II(atsm) treatment and control non-transgenic littermates, respectively. Error margins are S.E.M. in line plots (a, b), bar graphs (c, e-h), violin plots (j) and overall transcript signatures of individual animals (k), or 95% confidence interval of linear regression (dashed lines) in correlation plot (k). Solid lines in violin plots (j) represent median, dotted lines represent 25^th/75^th percentiles, truncated at min-max values. P values indicate significant differences between groups (c, d), significance of correlation (k), or significant difference between SOD1^G37R mice treated with or without Cu^II(atsm) (shaded area, b; e-h, j)