Tempol-mediated activation of latent iron regulatory protein activity prevents symptoms of neurodegenerative disease in IRP2 knockout mice
Tempol-mediated activation of latent iron regulatory protein activity prevents symptoms of neurodegenerative disease in IRP2 knockout mice
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DOI：
10.1073/pnas.0805361105
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发表时间：
2008-08-19
影响因子：
11.1
通讯作者：
Rouault, Tracey A.
中科院分区：
文献类型：
--
作者：
Ghosh, Manik C.;Tong, Wing-Hang;Rouault, Tracey A.
在哺乳动物中，两种同源的胞质调节蛋白，铁调节蛋白1（也称为IRP 1和Aco 1）和铁调节蛋白2（也称为IRP 2和Ireb 2），通过结合靶转录物内的铁响应元件（IRES）来感测胞质铁水平和转录后调节铁代谢基因，包括转铁蛋白受体1（TfR 1）和铁蛋白H和L亚基。缺乏IRP 2的小鼠会发生小细胞性贫血和神经退行性变，这与低TfR 1和高铁蛋白表达引起的功能性细胞铁耗竭有关。IRP 1基因敲除（IRP 1（-/-））动物不会显著失调铁代谢，部分原因是IRP 1是一种铁硫蛋白，在哺乳动物组织中主要起胞质乌头酸酶的作用，IRP 2活性增加以补偿IRP 1的IRE结合形式的损失。IRP 2（-/-）动物的神经退行性疾病随着动物年龄的增长而缓慢进展。在这项研究中，我们给IRP 2（-/-）小鼠喂食补充有稳定的氮氧化物Tempol的饮食，并显示神经肌肉损伤的进展明显减弱。在来源于IRP 2（-/-）动物的细胞系中，以及在Tempol饮食维持的动物的小脑、脑干和前脑中，IRP 1从胞质乌头酸酶转化为IRE结合蛋白，其稳定TfR 1转录物并抑制铁蛋白合成。我们认为Tempol通过分解IRP 1的胞浆铁硫簇和激活IRE结合活性来保护IRP 2（-/-）小鼠，这稳定了TfR 1转录物，抑制了铁蛋白合成，并部分恢复了脑中正常的细胞铁稳态。
In mammals, two homologous cytosolic regulatory proteins, iron regulatory protein 1 (also known as IRP1 and Aco1) and iron regulatory protein 2 (also known as IRP2 and Ireb2), sense cytosolic iron levels and posttranscriptionally regulate iron metabolism genes, including transferrin receptor 1 (TfR1) and ferritin H and L subunits, by binding to iron-responsive elements (IREs) within target transcripts. Mice that lack IRP2 develop microcytic anemia and neurodegeneration associated with functional cellular iron depletion caused by low TfR1 and high ferritin expression. IRP1 knockout (IRP1(-/-)) animals do not significantly misregulate iron metabolism, partly because IRP1 is an iron-sulfur protein that functions mainly as a cytosolic aconitase in mammalian tissues and IRP2 activity increases to compensate for loss of the IRE binding form of IRP1. The neurodegenerative disease of IRP2(-/-) animals progresses slowly as the animals age. In this study, we fed IRP2(-/-) mice a diet supplemented with a stable nitroxide, Tempol, and showed that the progression of neuromuscular impairment was markedly attenuated. In cell lines derived from IRP2(-/-) animals, and in the cerebellum, brainstem, and forebrain of animals maintained on the Tempol diet, IRP1 was converted from a cytosolic aconitase to an IRE binding protein that stabilized the TfR1 transcript and repressed ferritin synthesis. We suggest that Tempol protected IRP2(-/-) mice by disassembling the cytosolic iron-sulfur cluster of IRP1 and activating IRE binding activity, which stabilized the TfR1 transcript, repressed ferritin synthesis, and partially restored normal cellular iron homeostasis in the brain.