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SPY1 inhibits neuronal ferroptosis in amyotrophic lateral sclerosis by reducing lipid peroxidation through regulation of GCH1 and TFR1
Ferroptosis is an iron-dependent cell death with the accumulation of lipid peroxidation and dysfunction of antioxidant systems. As the critical regulator, glutathione peroxidase 4 (GPX4) has been demonstrated to be down-regulated in amyotrophic lateral sclerosis (ALS). However, the mechanism of ferr...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9950139/ https://www.ncbi.nlm.nih.gov/pubmed/36443440 http://dx.doi.org/10.1038/s41418-022-01089-7 |
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author | Wang, Di Liang, Weiwei Huo, Di Wang, Hongyong Wang, Ying Cong, Chaohua Zhang, Chunting Yan, Shi Gao, Ming Su, Xiaoli Tan, Xingli Zhang, Wenmo Han, Ling Zhang, Dongmei Feng, Honglin |
author_facet | Wang, Di Liang, Weiwei Huo, Di Wang, Hongyong Wang, Ying Cong, Chaohua Zhang, Chunting Yan, Shi Gao, Ming Su, Xiaoli Tan, Xingli Zhang, Wenmo Han, Ling Zhang, Dongmei Feng, Honglin |
author_sort | Wang, Di |
collection | PubMed |
description | Ferroptosis is an iron-dependent cell death with the accumulation of lipid peroxidation and dysfunction of antioxidant systems. As the critical regulator, glutathione peroxidase 4 (GPX4) has been demonstrated to be down-regulated in amyotrophic lateral sclerosis (ALS). However, the mechanism of ferroptosis in ALS remains unclear. In this research, bioinformatics analysis revealed a high correlation between ALS, ferroptosis, and Speedy/RINGO cell cycle regulator family member A (SPY1). Lipid peroxidation of ferroptosis in hSOD1G93A cells and mice was generated by TFR1-imported excess free iron, decreased GSH, mitochondrial membrane dysfunction, upregulated ALOX15, and inactivation of GCH1, GPX4. SPY1 is a “cyclin-like” protein that has been proved to enhance the viability of hSOD1(G93A) cells by inhibiting DNA damage. In our study, the decreased expression of SPY1 in ALS was resulted from unprecedented ubiquitination degradation mediated by MDM2 (a nuclear-localized E3 ubiquitin ligase). Further, SPY1 was identified as a novel ferroptosis suppressor via alleviating lipid peroxidation produced by dysregulated GCH1/BH4 axis (a resistance axis of ferroptosis) and transferrin receptor protein 1 (TFR1)-induced iron. Additionally, neuron-specific overexpression of SPY1 significantly delayed the occurrence and prolonged the survival in ALS transgenic mice through the above two pathways. These results suggest that SPY1 is a novel target for both ferroptosis and ALS. |
format | Online Article Text |
id | pubmed-9950139 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-99501392023-02-25 SPY1 inhibits neuronal ferroptosis in amyotrophic lateral sclerosis by reducing lipid peroxidation through regulation of GCH1 and TFR1 Wang, Di Liang, Weiwei Huo, Di Wang, Hongyong Wang, Ying Cong, Chaohua Zhang, Chunting Yan, Shi Gao, Ming Su, Xiaoli Tan, Xingli Zhang, Wenmo Han, Ling Zhang, Dongmei Feng, Honglin Cell Death Differ Article Ferroptosis is an iron-dependent cell death with the accumulation of lipid peroxidation and dysfunction of antioxidant systems. As the critical regulator, glutathione peroxidase 4 (GPX4) has been demonstrated to be down-regulated in amyotrophic lateral sclerosis (ALS). However, the mechanism of ferroptosis in ALS remains unclear. In this research, bioinformatics analysis revealed a high correlation between ALS, ferroptosis, and Speedy/RINGO cell cycle regulator family member A (SPY1). Lipid peroxidation of ferroptosis in hSOD1G93A cells and mice was generated by TFR1-imported excess free iron, decreased GSH, mitochondrial membrane dysfunction, upregulated ALOX15, and inactivation of GCH1, GPX4. SPY1 is a “cyclin-like” protein that has been proved to enhance the viability of hSOD1(G93A) cells by inhibiting DNA damage. In our study, the decreased expression of SPY1 in ALS was resulted from unprecedented ubiquitination degradation mediated by MDM2 (a nuclear-localized E3 ubiquitin ligase). Further, SPY1 was identified as a novel ferroptosis suppressor via alleviating lipid peroxidation produced by dysregulated GCH1/BH4 axis (a resistance axis of ferroptosis) and transferrin receptor protein 1 (TFR1)-induced iron. Additionally, neuron-specific overexpression of SPY1 significantly delayed the occurrence and prolonged the survival in ALS transgenic mice through the above two pathways. These results suggest that SPY1 is a novel target for both ferroptosis and ALS. Nature Publishing Group UK 2022-11-28 2023-02 /pmc/articles/PMC9950139/ /pubmed/36443440 http://dx.doi.org/10.1038/s41418-022-01089-7 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Wang, Di Liang, Weiwei Huo, Di Wang, Hongyong Wang, Ying Cong, Chaohua Zhang, Chunting Yan, Shi Gao, Ming Su, Xiaoli Tan, Xingli Zhang, Wenmo Han, Ling Zhang, Dongmei Feng, Honglin SPY1 inhibits neuronal ferroptosis in amyotrophic lateral sclerosis by reducing lipid peroxidation through regulation of GCH1 and TFR1 |
title | SPY1 inhibits neuronal ferroptosis in amyotrophic lateral sclerosis by reducing lipid peroxidation through regulation of GCH1 and TFR1 |
title_full | SPY1 inhibits neuronal ferroptosis in amyotrophic lateral sclerosis by reducing lipid peroxidation through regulation of GCH1 and TFR1 |
title_fullStr | SPY1 inhibits neuronal ferroptosis in amyotrophic lateral sclerosis by reducing lipid peroxidation through regulation of GCH1 and TFR1 |
title_full_unstemmed | SPY1 inhibits neuronal ferroptosis in amyotrophic lateral sclerosis by reducing lipid peroxidation through regulation of GCH1 and TFR1 |
title_short | SPY1 inhibits neuronal ferroptosis in amyotrophic lateral sclerosis by reducing lipid peroxidation through regulation of GCH1 and TFR1 |
title_sort | spy1 inhibits neuronal ferroptosis in amyotrophic lateral sclerosis by reducing lipid peroxidation through regulation of gch1 and tfr1 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9950139/ https://www.ncbi.nlm.nih.gov/pubmed/36443440 http://dx.doi.org/10.1038/s41418-022-01089-7 |
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