Rab6 is a Modulator of the Unfolded Protein Response: Implications for Alzheimer's Disease
Rab6 is a Modulator of the Unfolded Protein Response: Implications for Alzheimer's Disease
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DOI：
10.3233/jad-2011-110971
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发表时间：
2012-01-01
影响因子：
4
通讯作者：
Scheper, Wiep
中科院分区：
文献类型：
--
作者：
Elfrink, Hyung Lim;Zwart, Rob;Scheper, Wiep
未折叠蛋白反应（UPR）是内质网（ER）的应激反应，内质网是分泌途径的第一区室。UPR在阿尔茨海默病（AD）脑中的非缠结神经元中被激活，表明这是一种早期现象。我们发现，涉及分泌途径中的顺行和逆行运输的Rab 6的水平在AD患者的脑中增加。Rab 6的表达与UPR的激活程度密切相关，但不受UPR的控制。这表明Rab 6和UPR的激活都在AD的早期致病变化中增加。在这里，我们证明，Rab 6调节UPR，增加水平抑制而降低水平增强UPR诱导。Rab 6不参与UPR的初始阶段;它只在长时间ER应激后影响UPR。我们认为Rab 6参与了内质网应激损伤的恢复。AD大脑中Rab 6水平的增加与UPR激活相结合，表明未能从ER应激中恢复可能导致AD的神经退行性变。Rab 6介导的恢复途径可能提供了选择性抑制UPR破坏性途径的靶点。
The unfolded protein response (UPR) is a stress response of the endoplasmic reticulum (ER), the first compartment of the secretory pathway. The UPR is activated in non-tangle bearing neurons in Alzheimer's disease (AD) brain, indicating it is an early phenomenon. We found that the level of Rab6, implicated in anterograde and retrograde trafficking in the secretory pathway, is increased in brains of AD patients. Rab6 expression, closely correlated with the extent of UPR activation, is not controlled by the UPR. This suggests that Rab6 and UPR activation are both increased in response to early pathogenic changes in AD. Here we demonstrate that Rab6 modulates the UPR, increased levels inhibit whereas decreased levels augment UPR induction. Rab6 is not involved in the initial phase of the UPR; it only affects the UPR after prolonged ER stress. We propose that Rab6 is involved in the recovery from an ER stress insult. The increased Rab6 levels in AD brain in combination with UPR activation suggest that a failure to recover from ER stress may contribute to neurodegeneration in AD. The Rab6 mediated recovery pathway may provide a target to selectively inhibit the destructive pathways of the UPR.