Tau Accumulation Activates the Unfolded Protein Response by Impairing Endoplasmic Reticulum-Associated Degradation
Tau Accumulation Activates the Unfolded Protein Response by Impairing Endoplasmic Reticulum-Associated Degradation
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DOI：
10.1523/jneurosci.5397-12.2013
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发表时间：
2013-05-29
影响因子：
5.3
通讯作者：
Dickey, Chad A.
中科院分区：
文献类型：
--
作者：
Abisambra, Jose F.;Jinwal, Umesh K.;Dickey, Chad A.
在阿尔茨海默病（AD）中，神经元损失的机制在很大程度上仍然未知。虽然tau病理与神经元损失密切相关，但其积累如何导致神经毒性通路的激活尚不清楚。在这里，我们发现tau蛋白增加了大脑中泛素化蛋白的水平，并触发了未折叠蛋白反应（UPR）的激活。这表明tau干扰内质网（ER）中的蛋白质质量控制。与此一致，发现泛素与人AD脑和tau转基因（rTg4510）小鼠脑中的ER相关，但这并不总是与tau共定位。泛素化蛋白水平的增加伴随着磷酸化蛋白激酶R样ER激酶（pPERK）水平的增加，这是一种指示UPR激活的标志物。消耗细胞和脑中的可溶性tau水平可以逆转UPR激活。Tau的积累促进了其与ER膜和ER相关降解（ERAD）所必需的相关蛋白（包括含Valosin蛋白（VCP）和Hrd1）的有害相互作用。基于此，使用CD3 δ报告基因（ERAD底物）评估tau积累对ERAD效率的影响。事实上，CD3 δ在tau过表达和AD脑的体外和体内模型中积累。这些数据表明，可溶性tau损害ERAD，结果是激活UPR。然而，这一过程的可逆性表明，基于tau的治疗方法可以显著延迟这种类型的细胞死亡，从而延迟疾病进展。
In Alzheimer's disease (AD), the mechanisms of neuronal loss remain largely unknown. Although tau pathology is closely correlated with neuronal loss, how its accumulation may lead to activation of neurotoxic pathways is unclear. Here we show that tau increased the levels of ubiquitinated proteins in the brain and triggered activation of the unfolded protein response (UPR). This suggested that tau interferes with protein quality control in the endoplasmic reticulum (ER). Consistent with this, ubiquitin was found to associate with the ER in human AD brains and tau transgenic (rTg4510) mouse brains, but this was not always colocalized with tau. The increased levels of ubiquitinated protein were accompanied by increased levels of phosphorylated protein kinase R-like ER kinase (pPERK), a marker that indicates UPR activation. Depleting soluble tau levels in cells and brain could reverse UPR activation. Tau accumulation facilitated its deleterious interaction with ER membrane and associated proteins that are essential for ER-associated degradation (ERAD), including valosin-containing protein (VCP) and Hrd1. Based on this, the effects of tau accumulation on ERAD efficiency were evaluated using the CD3 delta reporter, an ERAD substrate. Indeed, CD3 delta accumulated in both in vitro and in vivo models of tau overexpression and AD brains. These data suggest that soluble tau impairs ERAD and the result is activation of the UPR. The reversibility of this process, however, suggests that tau-based therapeutics could significantly delay this type of cell death and therefore disease progression.