Protection from pathological tau by activation of the ER unfolded protein response

神经细胞中异常聚集的tau蛋白的病理性沉积是诊断之一 阿尔茨海默病(AD)和相关痴呆症(ADRD)的特征。病理性tau是如何导致 神经元的功能障碍和变性仍然是一个谜。然而，神经元功能障碍和 神经退化显然会导致痴呆症。要了解tau异常是如何导致 AD和ADRD的神经退行性变，我们在线虫中建立了一种转基因模型 由人类tau聚集引起的神经退行性变。在我们之前的工作中，我们确定了XBP-1、 未折叠蛋白反应的主要转录调节因子(UPR)，作为一种关键的调节因子 病理性tau蓄积和毒性。ER应激和UPR的激活显然是 被其他实验室牵连到人类肌萎缩侧索硬化症，尽管其功能后果 UPR激活对tau病理的影响尚不清楚。我们利用我们的线虫模型 肌萎缩侧索硬化症，剖析UPR在tau病理中的功能作用。我们已经发现了tau的病理 可以诱导内质网应激，而UPR的激活通过XBP-1对肌张力障碍有保护作用。我们 假设XBP-1s靶基因可以调节病理性tau的积累和清除。 为了验证这一假设，我们在没有内质网应激的情况下上调了神经元中的UPR，使用 表达外源基因的XBP-1s具有构成活性。对这个系统的转录研究已经 揭示了关键的XBP-1s靶基因，这些基因调节互变和与其他调节因子的串扰 普遍定期审议的分支机构(ATF6和PERK分支机构)。鉴于普遍定期审议的高度养护 哺乳动物和线虫之间的系统，我们建议利用现有的模型和转基因来 剖析UPR保护tau神经毒性的机制。的具体目标 本课题的主要目的是：1)确定XBP1s介导的细胞毒作用的分子机制 肌萎缩侧索硬化症；2)检查有助于tau清除和内质网相关的UPR分支串扰 降解，3)解决XBP-1S靶基因与神经变性的疾病相关性 人类疾病和小鼠的牵牛症模型。按计划完成该项目将 告知UPR参与牛磺酸疗法的分子机制。我们还将探索 XBP-1S的神经保护翻译潜能介导了哺乳动物脑内tau的清除。

Pathological deposition of abnormal aggregated tau protein in neurons is one of the diagnostic hallmarks of Alzheimer's disease (AD) and related dementia (ADRD). How pathological tau causes dysfunction and degeneration of neurons remains an enigma. However, neuronal dysfunction and neurodegeneration clearly cause dementia. To understand how abnormal tau contributes to neurodegeneration in AD and ADRD, we established a transgenic model in C. elegans for neurodegeneration driven by human tau aggregation. In our previous work, we identified XBP-1, the master transcriptional regulator of the unfolded protein response (UPR), as a critical regulator of pathological tau accumulation and toxicity. ER stress and activation of the UPR have clearly been implicated in human tauopathy disorders by other laboratories although the functional consequences of UPR activation on tau pathology remain unclear. We have leveraged our C. elegans model of tauopathy to dissect the functional role of the UPR in tau pathology. We have found that tau pathology can induce ER stress, and that UPR activation protects against tauopathy through XBP-1s. We hypothesize that XBP-1s target genes can modulate accumulation and clearance of pathological tau. To test this hypothesis, we upregulated the UPR in neurons in the absence of ER stress, using a constitutively active XBP-1s expressing transgene. Transcriptomic studies of this system have revealed key XBP-1s target genes that modulate tauopathy and cross talk with other regulatory branches of the UPR (ATF6 and PERK branches). Given the high level of conservation of the UPR system between mammals and C. elegans, we propose to utilize the existing model and transgenes to dissect the mechanism by which the UPR protects against tau neurotoxicity. The Specific Aims of this project are to: 1) Identify the molecular mechanisms of XBP1s mediated suppression of tauopathy; 2) Examine UPR branch crosstalk contributing to tau clearance and ER associated degradation, 3) Address the disease relevance of XBP-1s target genes to neurodegeneration in both human disease and mouse models of tauopathy. Completion of the project as proposed will inform the molecular mechanisms by which the UPR participates in tauopathy. We will also explore the neuroprotective translational potential of XBP-1s mediated tau clearance in the mammalian brain.