The unfolded protein response mediates reversible tau phosphorylation induced by metabolic stress.
The unfolded protein response mediates reversible tau phosphorylation induced by metabolic stress.
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DOI：
10.1038/cddis.2014.354
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发表时间：
2014-08-28
影响因子：
9
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中科院分区：
文献类型：
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未折叠蛋白反应（UPR）在神经退行性tau蛋白病如阿尔茨海默病（AD）中被激活，与tau病理学的早期阶段密切相关。代谢紊乱与AD风险增加密切相关，并且是UPR的有效诱导剂。在这里，我们证明了代谢应激通过激活UPR诱导内源性tau蛋白的磷酸化。令人惊讶的是，在恢复代谢稳态后，不仅UPR标志物pPERK、pIRE1α和BiP的水平，而且tau磷酸化在细胞模型以及休眠（一种体内生理低代谢模型）中都被逆转。使用全局UPR抑制剂TUDCA或PERK信号通路的特异性小分子抑制剂干预UPR，抑制代谢应激诱导的tau磷酸化。这些数据支持UPR介导的tau磷酸化作为对代谢应激的适应性反应的一部分的作用。不能恢复代谢稳态将导致延长的UPR激活和tau蛋白磷酸化，并因此可能有助于AD发病机制。我们证明了UPR在功能上参与了tau病理学的早期阶段。我们的数据表明，靶向UPR可用于tau相关神经退行性疾病的早期干预。
The unfolded protein response (UPR) is activated in neurodegenerative tauopathies such as Alzheimer's disease (AD) in close connection with early stages of tau pathology. Metabolic disturbances are strongly associated with increased risk for AD and are a potent inducer of the UPR. Here, we demonstrate that metabolic stress induces the phosphorylation of endogenous tau via activation of the UPR. Strikingly, upon restoration of the metabolic homeostasis, not only the levels of the UPR markers pPERK, pIRE1α and BiP, but also tau phosphorylation are reversed both in cell models as well as in torpor, a physiological hypometabolic model in vivo. Intervention in the UPR using the global UPR inhibitor TUDCA or a specific small-molecule inhibitor of the PERK signaling pathway, inhibits the metabolic stress-induced phosphorylation of tau. These data support a role for UPR-mediated tau phosphorylation as part of an adaptive response to metabolic stress. Failure to restore the metabolic homeostasis will lead to prolonged UPR activation and tau phosphorylation, and may thus contribute to AD pathogenesis. We demonstrate that the UPR is functionally involved in the early stages of tau pathology. Our data indicate that targeting of the UPR may be employed for early intervention in tau-related neurodegenerative diseases.
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通讯作者：
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Klann, Eric