Oligodendrocyte Death in Pelizaeus-Merzbacher Disease Is Rescued by Iron Chelation

• Published in: Cell stem cell Vol. 25; no. 4; pp. 531 - 541.e6
• Main Authors: Nobuta, Hiroko, Yang, Nan, Ng, Yi Han, Marro, Samuele G., Sabeur, Khalida, Chavali, Manideep, Stockley, John H., Killilea, David W., Walter, Patrick B., Zhao, Chao, Huie, Philip, Goldman, Steven A., Kriegstein, Arnold R., Franklin, Robin J.M., Rowitch, David H., Wernig, Marius
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.10.2019
• Subjects: Animals; Cell Differentiation; Cells, Cultured; Deferiprone - therapeutic use; Ferroptosis; gene correction; Humans; induced pluripotent stem cells; Induced Pluripotent Stem Cells - drug effects; Induced Pluripotent Stem Cells - physiology; Induced Pluripotent Stem Cells - transplantation; Iron - metabolism; Iron Chelating Agents - therapeutic use; iron chelation; leukodystrophy; Lipid Peroxidation; Mice; Mice, Mutant Strains; Mutation - genetics; Myelin Proteolipid Protein - genetics; Myelin Proteolipid Protein - metabolism; myelination; oligodendrocyte; Oligodendroglia - drug effects; Oligodendroglia - physiology; Oligodendroglia - transplantation; patient models; Pelizaeus-Merzbacher Disease - genetics; Pelizaeus-Merzbacher Disease - pathology; Pelizaeus-Merzbacher Disease - therapy; Stem Cell Transplantation; Targeted Gene Repair; patient models; ferroptosis; oligodendrocyte; iron chelation; myelination; leukodystrophy; induced pluripotent stem cells; gene correction
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2019.09.003

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. [Display omitted] •PLP1 mutations in Pelizaeus-Merzbacher disease cause iron-induced oligodendrocyte death•Gene correction in patient-derived iPSCs rescues PLP1 mutant oligodendrocyte cell death•Iron chelators and lipophilic antioxidants rescue mutant oligodendrocyte cell death Pelizaeus-Merzbacher disease is a pediatric leukodystrophy causing oligodendrocyte cell death. Nobuta et al. show that mutations in human PLP1 gene cause iron-induced cell death through lipid peroxidation, abnormal iron metabolism, and hypersensitivity to free iron. Iron chelation rescues cell death, offering a therapeutic direction for a disease without current treatments.