近日，美国斯坦福大学的Marius Wernig和加州大学旧金山分校的David H. Rowitch等研究人员合作发现，铁螯合可挽救佩梅病（Pelizaeus-Merzbacher disease，PMD）中少突胶质细胞的死亡。该项研究成果发表在2019年10月出版的《细胞—干细胞》上。

使用诱导性多能干细胞（iPSC）和基因校正，研究人员发现患者来源的少突胶质细胞可以发育到髓鞘形成前期，但随后会死亡。突变的少突胶质细胞显示了铁死亡的关键特征，包括脂质过氧化、异常的铁代谢和对游离铁的超敏反应。铁螯合能够挽救体外以及在体内移植后的突变体少突胶质细胞的凋亡、存活和分化。

最后，用小分子铁螯合剂去铁酮全身性治疗Plp1突变体Jimpy小鼠，能够减少少突胶质细胞凋亡并启动髓磷脂形成。因此，在PMD临床前模型中，铁螯合可以挽救少突胶质细胞铁诱导的细胞死亡和髓鞘形成。

据悉，PMD是X染色体连锁的脑白质营养不良，由PLP1基因（Proteolipid Protein 1）的突变引起，该蛋白编码一种主要的髓磷脂蛋白，该疾病导致严重的发育延迟和早期致死。先前的工作表明未折叠的蛋白反应和内质网应激途径参与其中，但PLP1基因型与表型之间很差的关联性提示其他致病机制。

附：英文原文

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

Author: Hiroko Nobuta, Nan Yang, Yi Han Ng, Samuele G. Marro, Khalida Sabeur, Manideep Chavali, John H. Stockley, David W. Killilea, Patrick B. Walter, Chao Zhao, Philip Huie, Steven A. Goldman, Arnold R. Kriegstein, Robin J.M. Franklin, David H. Rowitch, Marius Wernig

Issue&Volume: Volume 25 Issue 4

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 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.

DOI: 10.1016/j.stem.2019.09.003

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(19)30388-1