Oligodendrocyte Death in Pelizaeus-Merzbacher Disease Is Rescued by Iron Chelation.
Oligodendrocyte Death in Pelizaeus-Merzbacher Disease Is Rescued by Iron Chelation.
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DOI：
10.1016/j.stem.2019.09.003
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发表时间：
2019-10-03
期刊：
影响因子：
23.9
通讯作者：
Wernig M
中科院分区：
文献类型：
--
作者：
Nobuta H;Yang N;Ng YH;Marro SG;Sabeur K;Chavali M;Stockley JH;Killilea DW;Walter PB;Zhao C;Huie P Jr;Goldman SA;Kriegstein AR;Franklin RJM;Rowitch DH;Wernig M
Pelizaeus-Merzbacher病(PMD)是一种X连锁的脑白质营养不良，由蛋白质脂蛋白1(PLP1)突变引起，PLP1编码一种主要的髓鞘蛋白，导致严重的发育迟缓和早期死亡。以前的工作表明参与了未折叠蛋白反应(UPR)和内质网(ER)应激途径，但PLP1基因类型-表型相关性较差提示了其他致病机制。利用诱导多能干细胞(IPSC)和基因矫正，我们发现患者来源的少突胶质细胞可以发育到髓鞘前阶段，但随后经历细胞死亡。突变的少突胶质细胞表现出铁性下垂的主要特征，包括脂质过氧化，铁代谢异常，以及对游离铁过敏。铁螯合在体外和体内移植后均能挽救突变的少突胶质细胞的凋亡、存活和分化。最后，用小分子铁络合剂去铁酮对Plp1突变的Jimpy小鼠进行系统治疗，减少了少突胶质细胞的凋亡，并使髓鞘得以形成。因此，在PMD临床前模型中，少突胶质细胞铁诱导的细胞死亡和髓鞘形成可以通过铁络合来挽救。Pelizaeus-Merzbacher病是一种导致少突胶质细胞死亡的儿童脑白质营养不良症。Nobuta等人。研究表明，人类PLP1基因突变通过脂质过氧化、铁代谢异常和对游离铁的超敏反应导致铁诱导的细胞死亡。铁螯合作用挽救了细胞死亡，为目前没有治疗方法的疾病提供了治疗方向。
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 geno-type-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 differentiation in 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. 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.
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