Ferroptosis and Charcot–Marie–Tooth Disease 1A: Emerging Evidence for a Pathogenic Association
Charcot–Marie–Tooth disease (CMT) is the most common hereditary peripheral neuropathy worldwide, presenting clinically as muscle weakness that progresses to impaired ambulation or quadriplegia with age. CMT1A, the most common subtype, is caused by a duplication in PMP22, encoding an essential membra...
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MDPI AG
2025-03-01
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| author | Jacob B. White Kayla L. Sanchez Antonio Currais David Soriano-Castell Pamela Maher Salvador Soriano |
| author_facet | Jacob B. White Kayla L. Sanchez Antonio Currais David Soriano-Castell Pamela Maher Salvador Soriano |
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| description | Charcot–Marie–Tooth disease (CMT) is the most common hereditary peripheral neuropathy worldwide, presenting clinically as muscle weakness that progresses to impaired ambulation or quadriplegia with age. CMT1A, the most common subtype, is caused by a duplication in PMP22, encoding an essential membrane protein for Schwann cell myelin integrity. While the mechanisms of peripheral neurodegeneration in CMT1A are poorly understood, excessive oxidative stress, particularly lipid peroxidation, is a known pathological feature, and antioxidant therapy has reversed the CMT1A phenotype in a mouse model. For the first time, we define the pathogenic link between CMT1A and ferroptosis, a form of regulated cell death caused by excessive lipid peroxidation and hindered antioxidant defenses. Human-derived CMT1A fibroblasts showed greater susceptibility to RSL3, a pro-ferroptosis agent, compared with controls, alongside several ferroptosis markers, including elevated lipid peroxides and depleted GPX4, a critical anti-ferroptosis repressor. Similarly, transcriptomic analysis of human iPSC-derived Schwann cells revealed elevated ferroptosis activation and cellular stress markers in CMT1A. We propose that chronic, sublethal ferroptotic stress, mediated by lipid peroxide accumulation, depletes antioxidant defenses in CMT1A Schwann cells, leading to decompensation with age, manifesting as symptomatic disease. These results emphasize ferroptosis as a driver of CMT1A pathology, potentially revealing a new therapeutic path. |
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| institution | Kabale University |
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| language | English |
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| spelling | doaj-art-e7b4eb4b7f2041b091d800fafd9708d12025-08-20T03:43:51ZengMDPI AGAntioxidants2076-39212025-03-0114333110.3390/antiox14030331Ferroptosis and Charcot–Marie–Tooth Disease 1A: Emerging Evidence for a Pathogenic AssociationJacob B. White0Kayla L. Sanchez1Antonio Currais2David Soriano-Castell3Pamela Maher4Salvador Soriano5Department of Pathology and Human Anatomy, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USADepartment of Pathology and Human Anatomy, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USAThe Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USAThe Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USAThe Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USADepartment of Pathology and Human Anatomy, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USACharcot–Marie–Tooth disease (CMT) is the most common hereditary peripheral neuropathy worldwide, presenting clinically as muscle weakness that progresses to impaired ambulation or quadriplegia with age. CMT1A, the most common subtype, is caused by a duplication in PMP22, encoding an essential membrane protein for Schwann cell myelin integrity. While the mechanisms of peripheral neurodegeneration in CMT1A are poorly understood, excessive oxidative stress, particularly lipid peroxidation, is a known pathological feature, and antioxidant therapy has reversed the CMT1A phenotype in a mouse model. For the first time, we define the pathogenic link between CMT1A and ferroptosis, a form of regulated cell death caused by excessive lipid peroxidation and hindered antioxidant defenses. Human-derived CMT1A fibroblasts showed greater susceptibility to RSL3, a pro-ferroptosis agent, compared with controls, alongside several ferroptosis markers, including elevated lipid peroxides and depleted GPX4, a critical anti-ferroptosis repressor. Similarly, transcriptomic analysis of human iPSC-derived Schwann cells revealed elevated ferroptosis activation and cellular stress markers in CMT1A. We propose that chronic, sublethal ferroptotic stress, mediated by lipid peroxide accumulation, depletes antioxidant defenses in CMT1A Schwann cells, leading to decompensation with age, manifesting as symptomatic disease. These results emphasize ferroptosis as a driver of CMT1A pathology, potentially revealing a new therapeutic path.https://www.mdpi.com/2076-3921/14/3/331Charcot–Marie–ToothCMT1Aferroptosisperipheral neuropathyoxidative stressferroptotic stress |
| spellingShingle | Jacob B. White Kayla L. Sanchez Antonio Currais David Soriano-Castell Pamela Maher Salvador Soriano Ferroptosis and Charcot–Marie–Tooth Disease 1A: Emerging Evidence for a Pathogenic Association Antioxidants Charcot–Marie–Tooth CMT1A ferroptosis peripheral neuropathy oxidative stress ferroptotic stress |
| title | Ferroptosis and Charcot–Marie–Tooth Disease 1A: Emerging Evidence for a Pathogenic Association |
| title_full | Ferroptosis and Charcot–Marie–Tooth Disease 1A: Emerging Evidence for a Pathogenic Association |
| title_fullStr | Ferroptosis and Charcot–Marie–Tooth Disease 1A: Emerging Evidence for a Pathogenic Association |
| title_full_unstemmed | Ferroptosis and Charcot–Marie–Tooth Disease 1A: Emerging Evidence for a Pathogenic Association |
| title_short | Ferroptosis and Charcot–Marie–Tooth Disease 1A: Emerging Evidence for a Pathogenic Association |
| title_sort | ferroptosis and charcot marie tooth disease 1a emerging evidence for a pathogenic association |
| topic | Charcot–Marie–Tooth CMT1A ferroptosis peripheral neuropathy oxidative stress ferroptotic stress |
| url | https://www.mdpi.com/2076-3921/14/3/331 |
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