Inhibitory Act of Selenoprotein P on Cu+/Cu2+-Induced Tau Aggregation and Neurotoxicity
Inhibitory Act of Selenoprotein P on Cu+/Cu2+-Induced Tau Aggregation and Neurotoxicity
复制标题
DOI：
10.1021/ic501788v
复制
发表时间：
2014-10-20
影响因子：
4.6
通讯作者：
Liu, Qiong
中科院分区：
文献类型：
--
作者：
Du, Xiubo;Zheng, Youbiao;Liu, Qiong
阿尔茨海默病（AD）是一种神经退行性疾病，其特征是肽和蛋白质错误折叠和聚集，部分原因是存在过量的金属离子，如铜。淀粉样蛋白- β (A β)肽与铜离子的聚集和细胞毒性已被广泛研究；然而，金属化对tau蛋白的影响尚不清楚。在这里，我们研究了Cu+和Cu2+对tau微管结合域（tau- r2）第二重复单元的聚集和神经毒性的影响。结果表明，Tau-R2每个单体可结合0.44和0.34个Cu+，解离常数分别为1.1 nM和0.2 pM。铜在两种氧化状态下都刺激了tau-R2的聚集、ROS的产生和神经元细胞毒性。我们发现，铜相关的tau-R2聚集，降低了微管相关蛋白2 （MAP-2）和突触素的蛋白水平，降低了轴突的线粒体密度和流动性，从而损害了神经元的生长，也可能损害了神经元的功能。先前，我们报道了硒蛋白P （SelP-H）富含his的结构域，由于其金属螯合能力，抑制了金属诱导的A β聚集和毒性。在这里，我们证明了SelP-H不仅抑制铜介导的tau聚集，而且干扰正在进行的聚集并逆转已经形成的聚集。更有趣的是，SelP-H显著减弱Cu2+/Cu+-tau- r2诱导的细胞内ROS产生和神经元突触和线粒体运动的损伤。这项工作表明，表面暴露的富含his的SelP结构域使其能够调节Cu+/Cu2+介导的A β和tau的聚集和神经毒性，并可能在预防AD进展中发挥重要作用。
Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by peptide and protein misfolding and aggregation, in part due to the presence of excess metal ions such as copper. Aggregation and cytotoxicity of amyloid-beta (A beta) peptide with copper ion have been investigated extensively; however, the effects of metalation on tau are less known. Here, we presented the effects of Cu+ and Cu2+ on aggregation and neurotoxicity of the second repeat unit of the microtubule-binding domain of tau (tau-R2). Tau-R2 was demonstrated to bind 0.44 Cu2+ and 0.34 Cu+ per monomer with dissociation constants of 1.1 nM and 0.2 pM, respectively. Copper in both oxidation states stimulated the aggregation, ROS production, and neuronal cytotoxicity of tau-R2. We showed that copper-associated tau-R2 aggregates, decreased protein levels of microtubule-associated protein 2 (MAP-2), and synaptophysin in the primarily cultured cortical neurons, reduced mitochondrial density and mobility in the axon and, as a consequence, impaired the growth and probably also the function of neurons. Previously, we reported that the His-rich domain of selenoprotein P (SelP-H) inhibited metal-induced aggregation and toxicity of A beta, due to its metal chelation ability. Here we demonstrated that SelP-H not only inhibited copper-mediated tau aggregation but also interfered with the ongoing aggregation and reversed the already formed aggregates. More intriguing, SelP-H significantly attenuated Cu2+/Cu+-tau-R2-induced intracellular ROS production and the impairments of synapse and mitochondrial movement in neurons. This work implies that the surface-exposed His-rich domain of SelP makes it capable of modulating Cu+/Cu2+-mediated aggregation and neurotoxicity of both A beta and tau and may play important roles in the prevention of AD progression.