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Cell Stem Cell. 2019 Oct 3;25(4):531-541.e6. doi: 10.1016/j.stem.2019.09.003.

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

Author information

1
Department of Pediatrics, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
2
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
3
Department of Paediatrics, University of Cambridge, Hills Road, Cambridge, UK; Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Hills Road, Cambridge, UK.
4
Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA.
5
UCSF Benioff Children's Hospital Oakland, Oakland, CA 94609, USA; Department of Biology, University of Victoria, Victoria, BC, Canada.
6
Department of Clinical Neurosciences, University of Cambridge, Hills Road, Cambridge, UK; Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Hills Road, Cambridge, UK.
7
Department of Surgical Pathology, Stanford Health Care, Palo Alto, CA 94305, USA.
8
Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA; Center for Translational Neuromedicine, University of Copenhagen Faculty of Health, Copenhagen, Denmark.
9
Department of Pediatrics, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurology, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
10
Department of Pediatrics, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurosurgery, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Clinical Neurosciences, University of Cambridge, Hills Road, Cambridge, UK; Department of Paediatrics, University of Cambridge, Hills Road, Cambridge, UK; Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Hills Road, Cambridge, UK. Electronic address: dhr25@medschl.cam.ac.uk.
11
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: wernig@stanford.edu.

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.

KEYWORDS:

ferroptosis; gene correction; induced pluripotent stem cells; iron chelation; leukodystrophy; myelination; oligodendrocyte; patient models

PMID:
31585094
DOI:
10.1016/j.stem.2019.09.003

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