Hippocampal Subcellular Organelle Proteomic Alteration of Copper-Treated Mice
Hippocampal Subcellular Organelle Proteomic Alteration of Copper-Treated Mice
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铜处理小鼠海马亚细胞器蛋白质组改变
DOI：
10.1093/toxsci/kfy082
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发表时间：
2018-07
影响因子：
3.8
通讯作者：
Yang X
中科院分区：
文献类型：
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作者：
Yu H;Jiang X;Lin X;Zhang Z;Wu D;Zhou L;Liu J;Yang X
铜神经毒性与多种神经系统疾病有关。然而，人们对铜的神经毒性，特别是低剂量铜的神经毒性缺乏深入的认识。本研究采用二维荧光差凝胶电泳结合MALDI-TOF-MS/MS技术，研究了慢性低剂量铜处理（饮用水中氯化铜含量为0.13 ppm）对小鼠海马线粒体和核蛋白质组的影响。行为测试显示，低剂量的铜会导致空间记忆障碍、DNA氧化损伤以及突触蛋白的丧失。蛋白质组学分析显示，与未处理的小鼠相比，铜处理小鼠海马线粒体蛋白31种（15种增加，16种减少），海马核蛋白46种（18种增加，28种减少）受到调节。生物信息学分析表明，这些差异表达蛋白主要涉及能量代谢（NDUV1、COX5B、IDH3A和PGAM1）、突触（complexin-2、synapsin-2）、DNA损伤（PDIA3）、细胞凋亡（GRP75）和氧化应激（SODC、PRDX3）。在这些差异表达蛋白中，Western-blot分析证实突触相关蛋白synapsin-2显著降低。此外，我们发现铜离子靶蛋白超氧化物歧化酶[Cu-Zn] （SODC）在铜处理小鼠中比未处理小鼠降低。我们还发现，与未处理的小鼠相比，铜处理小鼠海马核中的镇静素（STMN1），一种微管不稳定的神经蛋白，显著减少。综上所述，我们得出结论，低剂量铜暴露会导致空间记忆障碍，并通过调节线粒体和核蛋白质组，特别是与呼吸链、突触囊泡融合、轴突/神经完整性和氧化应激相关的蛋白质，扰乱多种生物/致病过程。STMN1和SODC的变化可能是铜神经毒性的早期新生物标志物。
Copper neurotoxicity has been implicated in multiple neurological diseases. However, there is a lack of deep understanding on copper neurotoxicity, especially for low-dose copper exposure. In this study, we investigated the effects of chronic, low-dose copper treatment (0.13 ppm copper chloride in drinking water) on hippocampal mitochondrial and nuclear proteome in mice by 2-dimensional fluorescence difference gel electrophoresis coupled with MALDI-TOF-MS/MS. Behavioral tests revealed that low-dose copper caused spatial memory impairment, DNA oxidative damage as well as loss of synaptic proteins. Proteomic analysis revealed modulation of 31 hippocampal mitochondrial proteins (15 increased and 16 decreased), and 46 hippocampal nuclear proteins (18 increased and 28 decreased) in copper-treated versus untreated mice. Bioinformatic analysis indicated that these differentially expressed proteins are mainly involved energy metabolism (NDUV1, COX5B, IDH3A, and PGAM1), synapses (complexin-2, synapsin-2), DNA damage (PDIA3), apoptosis (GRP75), and oxidative stress (SODC, PRDX3). Among these differentially expressed proteins, synapsin-2, a synaptic-related protein, was found to be significantly decreased as confirmed by Western-blot analysis. In addition, we found that superoxide dismutase [Cu-Zn] (SODC), a copper ion target protein, was identified to be decreased in copper-treated mice versus untreated mice. We also found that stathmin (STMN1), a microtubule-destabilizing neuroprotein, was significantly decreased in hippocampal nuclei of copper-treated mice versus untreated mice. Taken together, we conclude that low-dose copper exposure causes spatial memory impairment and perturbs multiple biological/pathogenic processes by dysregulating the mitochondrial and nuclear proteome, particularly the proteins related to respiratory chain, synaptic vesicle fusion, axonal/neurtic integrity, and oxidative stress. The change of STMN1 and SODC may represent early novel biomarkers of copper neurotoxicity.
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影响因子：
--
作者：
E. Polazzi;Ilaria Mengoni;M. Caprini;Emiliano Pena-Altamira;E. Kurtys;Barbara Monti
通讯作者：
E. Polazzi;Ilaria Mengoni;M. Caprini;Emiliano Pena-Altamira;E. Kurtys;Barbara Monti
影响因子：
3.5
作者：
Voloboueva LA;Emery JF;Sun X;Giffard RG
通讯作者：
Giffard RG
影响因子：
4.4
作者：
S. Kim;T. Rhim
通讯作者：
S. Kim;T. Rhim
嗅球神经蛋白质组学揭示了在阿尔茨海默氏病进展过程中生存途径的时间顺序扰动和破坏防止蛋白复合物。
影响因子：
4.6
作者：
Lachén-Montes M;González-Morales A;Zelaya MV;Pérez-Valderrama E;Ausín K;Ferrer I;Fernández-Irigoyen J;Santamaría E
通讯作者：
Santamaría E
影响因子：
--
作者：
J. Grebb;P. Greengard
通讯作者：
J. Grebb;P. Greengard