Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran.
Department of Biology, Faculty of Sciences, University of Zabol, Zabol, Iran.
CNS Neurol Disord Drug Targets. 2021;20(5):451-464. doi: 10.2174/1871527320666210126114442.
In human tauopathies, pathological aggregation of misfolded/unfolded proteins, particularly microtubule-associated protein tau (MAPT, tau) is considered to be an essential mechanism that triggers the induction of endoplasmic reticulum (ER) stress.
Here, we assessed the molecular effects of natural antioxidant alpha-lipoic acid (ALA) in human tau (hTau)-induced ER unfolded protein response (ERUPR) in fruit flies.
In order to reduce hTau neurotoxicity during brain development, we used a transgenic model of tauopathy where the maximum toxicity was observed in adult flies. Then, the effects of ALA (0.001, 0.005, and 0.025% w/w of diet) in htau-induced ERUPR and behavioral dysfunctions in the ages 20 and 30 days were evaluated in Drosophila melanogaster.
Data from expression (mRNA and protein) patterns of htau, analysis of eyes external morphology as well as larvae olfactory memory were confirmed by our tauopathy model. Moreover, the expression of ERUPR-related proteins involving Activating Transcription Factor 6 (ATF6), inositol regulating enzyme 1 (IRE1), and protein kinase RNA-like ER kinase (PERK) wase upregulated and locomotor function decreased in both ages of the model flies. Remarkably, the lower dose of ALA modified ERUPR and supported the reduction of behavioral deficits in youngest adults through the enhancement of GRP87/Bip, reduction of ATF6, downregulation of PERK-ATF4 pathway, and activation of the IRE1-XBP1 pathway. On the other hand, only a higher dose of ALA affected the ERUPR via moderation of PERK-ATF4 signaling in the oldest adults. As ALA also exerts higher protective effects on the locomotor function of younger adults when htauis expressed in all neurons (htau-elav) and mushroom body neurons (htau-ok), we proposed that ALA has age-dependent effects in this model.
Taken together, based on our results, we conclude that aging potentially influences the ALA effective dose and mechanism of action on tau-induced ERUPR. Further molecular studies will warrant possible therapeutic applications of ALA in age-related tauopathies.
在人类 tau 病中，错误折叠/未折叠蛋白质的病理性聚集，特别是微管相关蛋白 tau（MAPT，tau）被认为是触发内质网（ER）应激的关键机制。
本研究旨在评估天然抗氧化剂α-硫辛酸（ALA）在人 tau（hTau）诱导的 ER 未折叠蛋白反应（ERUPR）中对果蝇的分子影响。
为了减少脑发育过程中 hTau 的神经毒性，我们使用了一种 tau 病的转基因模型，在成年果蝇中观察到最大的毒性。然后，在果蝇 20 日龄和 30 日龄时，评估了 ALA（饮食中 0.001%、0.005%和 0.025%w/w）对 htau 诱导的 ERUPR 和行为障碍的影响。
hTau 的表达（mRNA 和蛋白）模式、眼睛外部形态分析以及幼虫嗅觉记忆等数据均证实了我们的 tau 病模型。此外，涉及活化转录因子 6（ATF6）、肌醇需求酶 1（IRE1）和蛋白激酶 RNA 样内质网激酶（PERK）的 ERUPR 相关蛋白的表达上调，模型果蝇的运动功能下降。值得注意的是，较低剂量的 ALA 通过增强 GRP87/Bip、减少 ATF6、下调 PERK-ATF4 通路和激活 IRE1-XBP1 通路，改善了年轻成虫的 ERUPR，并支持了行为缺陷的减少。另一方面，只有较高剂量的 ALA 通过调节 PERK-ATF4 信号通路对老年成虫的 ERUPR 产生影响。由于 ALA 对 htau 在所有神经元（htau-elav）和蘑菇体神经元（htau-ok）中表达的年轻成虫的运动功能也具有更高的保护作用，我们提出，ALA 在该模型中具有年龄依赖性的作用。
综上所述，根据我们的结果，我们得出结论，衰老可能会影响 ALA 对 tau 诱导的 ERUPR 的有效剂量和作用机制。进一步的分子研究将保证 ALA 在与年龄相关的 tau 病中的可能治疗应用。
