Ndfip1 attenuated 6-OHDA-induced iron accumulation via regulating the degradation of DMT1
Ndfip1 attenuated 6-OHDA-induced iron accumulation via regulating the degradation of DMT1
复制标题
Ndfip1 通过调节 DMT1 的降解来减弱 6-OHDA 诱导的铁积累。
DOI：
10.1016/j.neurobiolaging.2014.10.021
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发表时间：
2015-02-01
影响因子：
4.2
通讯作者：
Xie, Junxia
中科院分区：
文献类型：
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作者：
Jia, Wenting;Xu, Huamin;Xie, Junxia
帕金森病（PD）患者黑质铁水平升高和二价金属转运蛋白1（DMT 1）表达增加已被报道。Nedd 4家族相互作用蛋白1（Ndfip 1）是泛素连接酶Nedd 4家族的一种衔接蛋白，在调节人皮层神经元DMT 1和铁稳态中发挥重要作用。在这项研究中，我们证明了在6-羟基多巴胺（6-OHDA）诱导的PD大鼠和6-OHDA处理的MES 23.5多巴胺能细胞中Ndfip 1的表达降低。进一步研究发现，在6-OHDA处理的MES 23.5细胞中，Ndfip 1的降低早于DMT 1 + IRE的升高，提示Ndfip 1的降低可能参与了DMT 1 + IRE的升高。此外，我们证明了Ndfip 1的过表达导致DMT 1 + IRE下调，导致铁内流减少和铁诱导的神经毒性。虽然Ndfip 1基因敲低导致DMT 1 + IRE蛋白水平降低，但部分加重了铁诱导的神经毒性。进一步的实验表明，6-OHDA诱导的Ndfip 1水平的降低可能与蛋白酶体和溶酶体激活以及6-OHDA引起的氧化应激有关。这些数据表明，Ndfip 1表达减少可能有助于6-OHDA诱导的铁积累的发病机制，Ndfip 1可以通过调节DMT 1的降解来减轻6-OHDA诱导的铁积累。(C)2015 Elsevier Inc. All rights reserved.
Elevated iron levels and increased expression of divalent metal transporter 1 (DMT1) in the substantia nigra of Parkinson's disease (PD) have been reported. Nedd4 family-interacting protein 1 (Ndfip1), an adaptor protein for the Nedd4 family of ubiquitin ligases, played an essential role in regulating DMT1 and iron homeostasis in human cortical neurons. In this study, we demonstrated that the expression of Ndfip1 decreased in 6-hydroxydopamine(6-OHDA)-induced PD rats and 6-OHDA-treated MES23.5 dopaminergic cells. Further study showed that the decrease of Ndfip1 occurred earlier than the increase of DMT1 with iron-responsive element (DMT1 + IRE) in 6-OHDA-treated MES23.5 cells, indicating that the decrease of Ndfip1 might be involved in the increase of DMT1 + IRE. In addition, we demonstrated that overexpression of Ndfip1 caused DMT1 + IRE downregulation, resulting in the decreased iron influx and iron-induced neurotoxicity. Although Ndfip1 knockdown led to decreased protein levels of DMT1 + IRE, partially aggravated iron-induced neurotoxicity. Further experiments showed that 6-OHDA-induced decrease in Ndfip1 levels might be related to proteasomal and lysosomal activations and oxidative stress caused by 6-OHDA. These data suggest that decreased Ndfip1 expression might contribute to the pathogenesis of 6-OHDA-induced iron accumulation and Ndfip1 could attenuate 6-OHDA-induced iron accumulation via regulating the degradation of DMT1. (C) 2015 Elsevier Inc. All rights reserved.