Essential role of POLDIP2 in Tau aggregation and neurotoxicity via autophagy/proteasome inhibition
Essential role of POLDIP2 in Tau aggregation and neurotoxicity via autophagy/proteasome inhibition
复制标题
DOI：
10.1016/j.bbrc.2015.04.084
复制
发表时间：
2015-06-26
影响因子：
3.1
通讯作者：
Jung, Yong-Keun
中科院分区：
文献类型：
--
作者：
Kim, YoungDoo;Park, Hyejin;Jung, Yong-Keun
在阿尔茨海默病和其他后遗症中，异常的Tau蛋白形成细胞内聚集体和Tau细丝。然而，调控Tau聚集的机制尚不完全清楚。在这篇文章中，我们证明了POLDIP2是一种新的Tau聚集调节因子。从基于细胞的表达文库筛选中，我们分离到了能增加Tau聚集的POLDIP2。神经细胞中POLDIP2的表达受多种应激的影响，包括Aβ、INF-α和H_2O_2。因此，POLDIP2的异位表达在不影响Tau磷酸化的情况下促进了Tau聚集体的形成，而POLDIP2的下调则减轻了ROS诱导的Tau聚集。有趣的是，我们发现POLDIP2过表达导致自噬活性和部分蛋白酶体活性的损害，并且这种活性保留在POLDIP2的DUF525结构域中。在人类紧张症的果蝇模型中，敲除果蝇POLDIP2同源基因CG12162，可以减弱Tau过度表达引起的粗眼表型。此外，通过CG12162基因敲除恢复了NERNAL-TAU(R406W)转基因文件的寿命。综上所述，这些观察表明POLDIP2通过损害自噬活性在Tau聚集中发挥关键作用，从而为深入了解Tau病理中的Tau聚集提供了线索。(C)2015 Elsevier Inc.保留所有权利。
In Alzheimer's disease and other tauopathy, abnormal Tau proteins form intracellular aggregates and Tau filaments. However, the mechanisms that regulate Tau aggregation are not fully understood. In this paper, we show that POLDIP2 is a novel regulator of Tau aggregation. From a cell-based screening using cDNA expression library, we isolated POLDIP2 which increased Tau aggregation. Expression of POLDIP2 was increased in neuronal cells by the multiple stresses, including A beta, INF-alpha and H2O2. Accordingly, ectopic expression of POLDIP2 enhanced the formation of Tau aggregates without affecting Tau phosphorylation, while down-regulation of POLDIP2 alleviated ROS-induced Tau aggregation. Interestingly, we found that POLDIP2 overexpression induced impairments of autophagy activity and partially proteasome activity and this activities were retained in DUF525 domain of POLDIP2. In a drosophila model of human tauopathy, knockdown of the drosophila POLDIP2 homolog, CG12162, attenuated rough eye phenotype induced by Tau overexpression. Further, the lifespan of neural-Tau(R406W) transgenic files were recovered by CG12162 knockdown. Together, these observations indicate that POLDIP2 plays a crucial role in Tau aggregation via the impairment of autophagy activity, providing insight into Tau aggregation in Tau pathology. (C) 2015 Elsevier Inc. All rights reserved.