Unfolded protein response activation protects neurons against pathological tau

 描述(申请人提供)：含有异常聚集的tau蛋白的神经元损伤是阿尔茨海默病(AD)、相关的肌萎缩侧索硬化症和大脑高级衰老的诊断标志之一。聚集的tau是如何导致AD患者神经元功能障碍和丢失的仍是个谜，尽管神经元功能障碍和丢失显然会导致痴呆。为了更好地了解tau异常在AD和其他tau病中如何促进神经退化，我们在线虫中建立了一个由人tau聚集驱动的神经退化的转基因模型。通过对tau神经毒性相关基因的研究，我们已经确定了XBP1，它是未折叠蛋白反应(UPR)的主要转录调节因子。尽管UPR激活对tau病理的功能影响尚不清楚，但其他实验室已明确认为内质网应激和UPR的激活与人类的肌张力障碍有关。我们利用我们的秀丽线虫的牛磺酸病变模型来剖析UPR在牛磺酸病理中的功能作用。虽然缺乏XBP1功能的线虫在正常条件下是存活的，但当受到内质网应激时，它们会死亡。同样，表达人tau但缺乏XBP1的线虫是不可行的。这些发现提示tau病理诱导了内质网应激，而UPR的激活对tau病具有保护作用。为了验证这一假设，我们使用结构性活跃的XBP1转基因，在没有内质网应激的情况下上调了神经元中的UPR。初步数据表明，具有结构性活性的XBP1足以预防与直肠病相关的表型，这支持了UPR具有预防直肠病的作用的论点。到目前为止收集的数据还没有涉及UPR激活如何预防紧张症的机制。鉴于哺乳动物和线虫之间UPR系统的高度保守，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。虽然这一机制似乎是通过XBP1靶基因介导的，但其分子基础仍不清楚。该项目的具体目的是：确定哪些XBP1靶基因调控tau介导的神经元功能障碍和神经变性，剖析这些靶基因调控tau病的机制，并确定UPR的所有三个分支是否全面参与保护tau毒性。根据建议的项目完成，将确定特定的基因和正常功能的途径，以解毒tau病理。新调节剂的发现将为该领域提供更多的调节点，这将为将来在小鼠模型中进行ta介导的神经变性和UPR介导的神经保护的翻译研究奠定基础。

 DESCRIPTION (provided by applicant): Neuronal lesions containing abnormal aggregated tau protein are one of the diagnostic hallmarks of Alzheimer's disease (AD), related tauopathy disorders, and advanced aging of the brain. How aggregated tau leads to the dysfunction and loss of neurons in AD patients remains enigmatic, although neuronal dysfunction and loss clearly causes dementia. To better understand how abnormal tau contributes to neurodegeneration in AD and other tauopathies, we established a transgenic model in C. elegans for neurodegeneration driven by human tau aggregation. Through investigation of the genes involved in tau neurotoxicity, we have identified XBP1, the master transcriptional regulator of the unfolded protein response (UPR). 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. While C. elegans lacking XBP1 function are viable under normal conditions, when challenged with ER stress they die. Likewise C. elegans expressing human tau but lacking XBP1 are not viable. These findings suggest tau pathology induces ER stress, and UPR activation protects against tauopathy. To test this hypothesis, we upregulated the UPR in the absence of ER stress specifically in neurons using a constitutively active XBP1 transgene. Preliminary data indicates constitutively active XBP1 suffices to protect against tauopathy related phenotypes bolstering the argument for the UPR acting to protect against tauopathy. The data gathered to date do not address the mechanism of how UPR activation protects against tauopathy. 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. While the mechanism appears to be mediated through XBP1 target genes, the molecular underpinnings remain unclear. The Specific Aims of this project are to: identify which XBP1 target genes modulate tau mediated neuronal dysfunction and neurodegeneration, dissect the mechanism by which these target genes regulate tauopathy, and determine whether or not there is comprehensive engagement of all three branches of the UPR in protecting against tau toxicity. Completion of the project as proposed will identify specific genes and pathways normally functioning to detoxify tau pathology. Identification of new regulators of tauopathy will provide the field with additional points of intervention in tauopathy which will set the stage for future translational studies of ta mediated neurodegeneration and UPR mediated neuroprotection in mouse models.