Iron accumulates in Huntington's disease neurons: protection by deferoxamine.
Iron accumulates in Huntington's disease neurons: protection by deferoxamine.
复制标题
DOI：
10.1371/journal.pone.0077023
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Fox JH
中科院分区：
文献类型：
--
作者：
Chen J;Marks E;Lai B;Zhang Z;Duce JA;Lam LQ;Volitakis I;Bush AI;Hersch S;Fox JH
亨廷顿病 (HD) 是一种进行性神经退行性疾病，由亨廷顿基因中编码多聚谷氨酰胺的 CAG 扩增引起。铁在 HD 患者和小鼠疾病模型的大脑中积聚。然而，铁积累的细胞和亚细胞位点以及对疾病进展的重要性尚不清楚。我们使用独立的方法来研究脑铁积累的位置。在 R6/2 HD 小鼠大脑中，同步加速器 X 射线荧光分析显示，纹状体神经元核周细胞质中铁以离散点的形式积累。此外，二价铁 (II) 灌注特恩布尔染色结合透射电子显微镜超微结构分析显示，R6/2 HD 纹状体神经元中膜结合核周囊泡的染色增加。对 R6/2 HD 小鼠铁稳态蛋白的分析显示，铁反应蛋白（IRP 1 和 2）水平降低，铁摄取转铁蛋白受体 (TfR) 表达相应降低，神经元铁输出蛋白铁转运蛋白 (FPN) 水平升高。最后，我们表明，心室内递送铁螯合剂去铁胺可改善 R6/2 HD 小鼠的运动表型。我们的数据支持小鼠 HD 神经元内吞/溶酶体室中氧化还原活性亚铁的积累。 IRP、TfR 和 FPN 的表达变化与神经元内不稳定铁库增加的代偿反应一致，导致对铁相关氧化应激的易感性增加。这些发现与去铁胺的保护作用一起支持神经元铁积累在 HD 中的增强作用。
Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by a polyglutamine-encoding CAG expansion in the huntingtin gene. Iron accumulates in the brains of HD patients and mouse disease models. However, the cellular and subcellular sites of iron accumulation, as well as significance to disease progression are not well understood. We used independent approaches to investigate the location of brain iron accumulation. In R6/2 HD mouse brain, synchotron x-ray fluorescence analysis revealed iron accumulation as discrete puncta in the perinuclear cytoplasm of striatal neurons. Further, perfusion Turnbull’s staining for ferrous iron (II) combined with transmission electron microscope ultra-structural analysis revealed increased staining in membrane bound peri-nuclear vesicles in R6/2 HD striatal neurons. Analysis of iron homeostatic proteins in R6/2 HD mice revealed decreased levels of the iron response proteins (IRPs 1 and 2) and accordingly decreased expression of iron uptake transferrin receptor (TfR) and increased levels of neuronal iron export protein ferroportin (FPN). Finally, we show that intra-ventricular delivery of the iron chelator deferoxamine results in an improvement of the motor phenotype in R6/2 HD mice. Our data supports accumulation of redox-active ferrous iron in the endocytic / lysosomal compartment in mouse HD neurons. Expression changes of IRPs, TfR and FPN are consistent with a compensatory response to an increased intra-neuronal labile iron pool leading to increased susceptibility to iron-associated oxidative stress. These findings, together with protection by deferoxamine, support a potentiating role of neuronal iron accumulation in HD.
登录
查看更多内容
影响因子：
5.3
作者：
Jeong, Suh Young;Rathore, Khizr I.;David, Samuel
通讯作者：
David, Samuel
影响因子：
64.5
作者：
Duce JA;Tsatsanis A;Cater MA;James SA;Robb E;Wikhe K;Leong SL;Perez K;Johanssen T;Greenough MA;Cho HH;Galatis D;Moir RD;Masters CL;McLean C;Tanzi RE;Cappai R;Barnham KJ;Ciccotosto GD;Rogers JT;Bush AI
通讯作者：
Bush AI
影响因子：
29
作者：
Donovan, A;Lima, CA;Andrews, NC
通讯作者：
Andrews, NC
影响因子：
5.4
作者：
Firdaus, Wance J. J.;Wyttenbach, Andreas;Arrigo, Andre-Patrick
通讯作者：
Arrigo, Andre-Patrick
影响因子：
4.8
作者：
Guo, Qinxi;Li, Hongmei;Zheng, Hui
通讯作者：
Zheng, Hui