Chongqing Key Lab of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing, 400054, China.
Chongqing Key Lab of Catalysis & Functional Organic Molecules, Chongqing Technology and Business University, Chongqing, 400067, China.
Neurochem Res. 2018 Mar;43(3):669-680. doi: 10.1007/s11064-018-2469-z. Epub 2018 Feb 9.
Altered proteostasis induced by amyloid peptide aggregation and hyperphosphorylation of tau protein, is a prominent feature of Alzheimer's disease, which highlights the occurrence of endoplasmic reticulum stress and triggers the activation of the unfolded protein response (UPR), a signaling pathway that enforces adaptive programs to sustain proteostasis. In this study, we investigated the role of geniposide in the activation of UPR induced by high glucose in primary cortical neurons. We found that high glucose induced a significant activation of UPR, and geniposide enhanced the effect of high glucose on the phosphorylation of IRE1α, the most conserved UPR signaling branch. We observed that geniposide induced the expression of HRD1, an ubiquitin-ligase E3 in a time dependent manner, and amplified the expression of HRD1 induced by high glucose in primary cortical neurons. Suppression of IRE1α activity with STF-083010, an inhibitor of IRE1 phosphorylation, prevented the roles of geniposide on the expression of HRD1 and APP degradation in high glucose-treated cortical neurons. In addition, the results from RNA interfere on HRD1 revealed that HRD1 was involved in geniposide regulating APP degradation in cortical neurons. These data suggest that geniposide might be benefit to re-establish proteostasis by enhancing the UPR to decrease the load of APP in neurons challenged by high glucose.
淀粉样肽聚集和 tau 蛋白过度磷酸化引起的蛋白质稳态改变，是阿尔茨海默病的一个显著特征，这突出了内质网应激的发生，并触发未折叠蛋白反应 (UPR) 的激活，这是一种信号通路，可强制实施适应性程序以维持蛋白质稳态。在这项研究中，我们研究了京尼平苷在高葡萄糖诱导的原代皮质神经元 UPR 激活中的作用。我们发现高葡萄糖诱导 UPR 显著激活，京尼平苷增强了高葡萄糖对 IRE1α磷酸化的作用，IRE1α是最保守的 UPR 信号分支。我们观察到京尼平苷以时间依赖性方式诱导 HRD1 的表达，一种泛素连接酶 E3，并放大高葡萄糖诱导的原代皮质神经元中 HRD1 的表达。用 STF-083010（IRE1 磷酸化抑制剂）抑制 IRE1α活性可阻止京尼平苷在高葡萄糖处理的皮质神经元中对 HRD1 和 APP 降解的作用。此外，HRD1 的 RNA 干扰结果表明 HRD1 参与了京尼平苷调节皮质神经元中 APP 降解。这些数据表明，京尼平苷可能通过增强 UPR 来减轻高葡萄糖刺激的神经元中 APP 的负荷，从而有助于重新建立蛋白质稳态。
