Oligodendrocyte Death in Pelizaeus-Merzbacher Disease Is Rescued by Iron Chelation.
Cell Stem Cell
; 25(4): 531-541.e6, 2019 Oct 03.
Article
em En
| MEDLINE
| ID: mdl-31585094
ABSTRACT
Pelizaeus-Merzbacher disease (PMD) is an X-linked leukodystrophy caused by mutations in Proteolipid Protein 1 (PLP1), encoding a major myelin protein, resulting in profound developmental delay and early lethality. Previous work showed involvement of unfolded protein response (UPR) and endoplasmic reticulum (ER) stress pathways, but poor PLP1 genotype-phenotype associations suggest additional pathogenetic mechanisms. Using induced pluripotent stem cell (iPSC) and gene-correction, we show that patient-derived oligodendrocytes can develop to the pre-myelinating stage, but subsequently undergo cell death. Mutant oligodendrocytes demonstrated key hallmarks of ferroptosis including lipid peroxidation, abnormal iron metabolism, and hypersensitivity to free iron. Iron chelation rescued mutant oligodendrocyte apoptosis, survival, and differentiationin vitro, and post-transplantation in vivo. Finally, systemic treatment of Plp1 mutant Jimpy mice with deferiprone, a small molecule iron chelator, reduced oligodendrocyte apoptosis and enabled myelin formation. Thus, oligodendrocyte iron-induced cell death and myelination is rescued by iron chelation in PMD pre-clinical models.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
6_ODS3_enfermedades_notrasmisibles
Base de dados:
MEDLINE
Assunto principal:
Oligodendroglia
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Quelantes de Ferro
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Proteína Proteolipídica de Mielina
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Doença de Pelizaeus-Merzbacher
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Células-Tronco Pluripotentes Induzidas
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Deferiprona
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Ferro
Limite:
Animals
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Humans
Idioma:
En
Revista:
Cell Stem Cell
Ano de publicação:
2019
Tipo de documento:
Article