Oligodendrocyte Death in Pelizaeus-Merzbacher Disease Is Rescued by Iron Chelation. Nobuta, H., Yang, N., Ng, Y. H., Marro, S. G, Sabeur, K., Chavali, M., Stockley, J. H, Killilea, D. W, Walter, P. B, Zhao, C., Huie, J., Goldman, S. A, Kriegstein, A. R, Franklin, R. J M, Rowitch, D. H, & Wernig, M. Cell Stem Cell, 25(4):531–541.e6, October, 2019. abstract bibtex 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.
@ARTICLE{Nobuta2019-ss,
title = "Oligodendrocyte Death in {Pelizaeus-Merzbacher} Disease Is
Rescued by Iron Chelation",
author = "Nobuta, Hiroko and Yang, Nan and Ng, Yi Han and Marro, Samuele G
and Sabeur, Khalida and Chavali, Manideep and Stockley, John H
and Killilea, David W and Walter, Patrick B and Zhao, Chao and
Huie, Jr, Philip and Goldman, Steven A and Kriegstein, Arnold R
and Franklin, Robin J M and Rowitch, David H and Wernig, Marius",
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.",
journal = "Cell Stem Cell",
volume = 25,
number = 4,
pages = "531--541.e6",
month = oct,
year = 2019,
keywords = "ferroptosis; gene correction; induced pluripotent stem cells;
iron chelation; leukodystrophy; myelination; oligodendrocyte;
patient models",
language = "en"
}
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H","Wernig, M."],"bibdata":{"bibtype":"article","type":"article","title":"Oligodendrocyte Death in Pelizaeus-Merzbacher Disease Is Rescued by Iron Chelation","author":[{"propositions":[],"lastnames":["Nobuta"],"firstnames":["Hiroko"],"suffixes":[]},{"propositions":[],"lastnames":["Yang"],"firstnames":["Nan"],"suffixes":[]},{"propositions":[],"lastnames":["Ng"],"firstnames":["Yi","Han"],"suffixes":[]},{"propositions":[],"lastnames":["Marro"],"firstnames":["Samuele","G"],"suffixes":[]},{"propositions":[],"lastnames":["Sabeur"],"firstnames":["Khalida"],"suffixes":[]},{"propositions":[],"lastnames":["Chavali"],"firstnames":["Manideep"],"suffixes":[]},{"propositions":[],"lastnames":["Stockley"],"firstnames":["John","H"],"suffixes":[]},{"propositions":[],"lastnames":["Killilea"],"firstnames":["David","W"],"suffixes":[]},{"propositions":[],"lastnames":["Walter"],"firstnames":["Patrick","B"],"suffixes":[]},{"propositions":[],"lastnames":["Zhao"],"firstnames":["Chao"],"suffixes":[]},{"propositions":[],"lastnames":["Huie"],"firstnames":["Jr"],"suffixes":["Philip"]},{"propositions":[],"lastnames":["Goldman"],"firstnames":["Steven","A"],"suffixes":[]},{"propositions":[],"lastnames":["Kriegstein"],"firstnames":["Arnold","R"],"suffixes":[]},{"propositions":[],"lastnames":["Franklin"],"firstnames":["Robin","J","M"],"suffixes":[]},{"propositions":[],"lastnames":["Rowitch"],"firstnames":["David","H"],"suffixes":[]},{"propositions":[],"lastnames":["Wernig"],"firstnames":["Marius"],"suffixes":[]}],"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.","journal":"Cell Stem Cell","volume":"25","number":"4","pages":"531–541.e6","month":"October","year":"2019","keywords":"ferroptosis; gene correction; induced pluripotent stem cells; iron chelation; leukodystrophy; myelination; oligodendrocyte; patient models","language":"en","bibtex":"@ARTICLE{Nobuta2019-ss,\n title = \"Oligodendrocyte Death in {Pelizaeus-Merzbacher} Disease Is\n Rescued by Iron Chelation\",\n author = \"Nobuta, Hiroko and Yang, Nan and Ng, Yi Han and Marro, Samuele G\n and Sabeur, Khalida and Chavali, Manideep and Stockley, John H\n and Killilea, David W and Walter, Patrick B and Zhao, Chao and\n Huie, Jr, Philip and Goldman, Steven A and Kriegstein, Arnold R\n and Franklin, Robin J M and Rowitch, David H and Wernig, Marius\",\n abstract = \"Pelizaeus-Merzbacher disease (PMD) is an X-linked leukodystrophy\n caused by mutations in Proteolipid Protein 1 (PLP1), encoding a\n major myelin protein, resulting in profound developmental delay\n and early lethality. Previous work showed involvement of unfolded\n protein response (UPR) and endoplasmic reticulum (ER) stress\n pathways, but poor PLP1 genotype-phenotype associations suggest\n additional pathogenetic mechanisms. Using induced pluripotent\n stem cell (iPSC) and gene-correction, we show that\n patient-derived oligodendrocytes can develop to the\n pre-myelinating stage, but subsequently undergo cell death.\n Mutant oligodendrocytes demonstrated key hallmarks of ferroptosis\n including lipid peroxidation, abnormal iron metabolism, and\n hypersensitivity to free iron. Iron chelation rescued mutant\n oligodendrocyte apoptosis, survival, and differentiationin vitro,\n and post-transplantation in vivo. Finally, systemic treatment of\n Plp1 mutant Jimpy mice with deferiprone, a small molecule iron\n chelator, reduced oligodendrocyte apoptosis and enabled myelin\n formation. Thus, oligodendrocyte iron-induced cell death and\n myelination is rescued by iron chelation in PMD pre-clinical\n models.\",\n journal = \"Cell Stem Cell\",\n volume = 25,\n number = 4,\n pages = \"531--541.e6\",\n month = oct,\n year = 2019,\n keywords = \"ferroptosis; gene correction; induced pluripotent stem cells;\n iron chelation; leukodystrophy; myelination; oligodendrocyte;\n patient models\",\n language = \"en\"\n}\n\n","author_short":["Nobuta, H.","Yang, N.","Ng, Y. H.","Marro, S. G","Sabeur, K.","Chavali, M.","Stockley, J. H","Killilea, D. W","Walter, P. B","Zhao, C.","Huie, J.","Goldman, S. A","Kriegstein, A. R","Franklin, R. J M","Rowitch, D. 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