School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin, 150001, China; Department of Bioengineering, Harbin Institute of Technology, Weihai, 264209, China.
School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin, 150001, China; Department of Bioengineering, Harbin Institute of Technology, Weihai, 264209, China.
Eur J Pharmacol. 2024 Nov 15;983:176962. doi: 10.1016/j.ejphar.2024.176962. Epub 2024 Aug 28.
The accumulation of misfolded proteins is a common pathological characteristic shared by many neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. The disruption of proteostasis triggers endoplasmic reticulum (ER) stress, during which the unfolded protein response (UPR) is initiated by the activation of protein kinase R-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1) and activating transcription factor 6 (ATF6). These three branches of UPR signals act in concert to reduce the levels of abnormal proteins and restore ER homeostasis. However, the overactivation of UPR impairs cell function and induces apoptosis, which has been implicated in neurodegeneration. Astaxanthin is a xanthophyll carotenoid which has been shown to have neuroprotective effects in both cell and animal models; however, its effects on ER stress and UPR induced by disrupted proteostasis remain unclear. In this study, the effects of astaxanthin on ER stress and cytotoxicity were investigated in N2a cells stably expressing the pro-aggregant tau repeat domain carrying FTDP-17 mutation ΔK280 (TauΔK280). The results demonstrated that astaxanthin significantly inhibited TauΔK280-induced loss of cell viability and apoptosis, attenuating TauΔK280-induced caspase-3 activation and decrease of Bcl-2. Further studies revealed that astaxanthin treatment alleviated TauΔK280-induced ER stress and suppressed the activation of PERK, IRE1 and ATF6 signaling pathways. These findings suggested that astaxanthin might inhibit TauΔK280-induced cytotoxicity by attenuating UPR and ER stress. In addition, astaxanthin treatment resulted in a great reduction in the production of intracellular reactive oxygen species and a significant decrease in calcium influx induced by TauΔK280, which also contributed to the protective effects of astaxanthin against TauΔK280-induced cytotoxicity.
蛋白质错误折叠的积累是包括阿尔茨海默病和帕金森病在内的许多神经退行性疾病的共同病理特征。蛋白质稳态的破坏会引发内质网（ER）应激，在此期间，未折叠蛋白反应（UPR）通过蛋白激酶 R 样内质网激酶（PERK）、肌醇需求酶 1（IRE1）和激活转录因子 6（ATF6）的激活而启动。UPR 的这三个分支协同作用以降低异常蛋白质的水平并恢复 ER 稳态。然而，UPR 的过度激活会损害细胞功能并诱导细胞凋亡，这与神经退行性变有关。虾青素是一种叶黄素类胡萝卜素，已在细胞和动物模型中显示出神经保护作用；然而，其对由蛋白质稳态破坏引起的 ER 应激和 UPR 的影响尚不清楚。在这项研究中，研究了虾青素对稳定表达携带 FTDP-17 突变 ΔK280（TauΔK280）聚集性 tau 重复结构域的 N2a 细胞中 ER 应激和细胞毒性的影响。结果表明，虾青素显著抑制 TauΔK280 诱导的细胞活力丧失和细胞凋亡，减弱 TauΔK280 诱导的半胱天冬酶-3 激活和 Bcl-2 减少。进一步的研究表明，虾青素处理减轻了 TauΔK280 诱导的 ER 应激，并抑制了 PERK、IRE1 和 ATF6 信号通路的激活。这些发现表明，虾青素可能通过减弱 UPR 和 ER 应激来抑制 TauΔK280 诱导的细胞毒性。此外，虾青素处理导致 TauΔK280 诱导的细胞内活性氧产生大大减少，钙流入显著减少，这也有助于虾青素对 TauΔK280 诱导的细胞毒性的保护作用。
