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

通过激活 ER 未折叠蛋白反应来预防病理性 tau 蛋白

• 批准号: 9901055
• 负责人: Brian C. Kraemer
• 金额: $ 53万
• 依托单位: SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9901055
• 关键词: ATF6 gene; Address; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Animal Model; Animals; Bioinformatics; Brain; Caenorhabditis elegans; Cellular Stress; Cessation of life; Dementia; Deposition; Diagnostic; Disease; Disease model; Endoplasmic Reticulum; Estrogen receptor positive; Exhibits; Frontotemporal Lobar Degenerations; Functional disorder; Future; Genes; Genetic Transcription; Goals; Human; Laboratories; Lesion; Mammals; Mediating; Modeling; Molecular; Molecular Genetics; Molecular Target; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuronal Dysfunction; Neurons; Pathologic; Pathology; Patients; Phenotype; Progressive Supranuclear Palsy; Protein Isoforms; Proteins; Role; System; Tauopathies; Testing; Toxic effect; Transgenes; Transgenic Model; Transgenic Organisms; Work; XBP1 gene; brain tissue; effective therapy; endoplasmic reticulum stress; genome wide association study; human disease; hyperphosphorylated tau; misfolded protein; mouse model; neuroprotection; neurotoxicity; premature; response; response biomarker; tau Proteins; tau aggregation; tau mutation; transcriptomics; translational study

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.

神经元中异常聚集的 tau 蛋白的病理沉积是诊断的依据之一 阿尔茨海默病 (AD) 和相关痴呆 (ADRD) 的特征。病理性 tau 蛋白是如何引起的 神经元功能障碍和退化仍然是一个谜。然而，神经元功能障碍和 神经退行性疾病显然会导致痴呆。了解异常 tau 蛋白如何促成 AD 和 ADRD 中的神经退行性疾病，我们在秀丽隐杆线虫中建立了转基因模型 由人类 tau 蛋白聚集驱动的神经退行性疾病。在我们之前的工作中，我们确定了 XBP-1， 未折叠蛋白反应（UPR）的主要转录调节因子，作为 病理性 tau 积累和毒性。 ER 应激和 UPR 激活已被明确 其他实验室认为与人类 tau 蛋白病相关，但功能性后果 UPR 激活对 tau 病理学的影响仍不清楚。我们利用了我们的线虫模型 tau 蛋白病剖析 UPR 在 tau 蛋白病理学中的功能作用。我们发现 tau 病理学 可以诱导 ER 应激，UPR 激活可通过 XBP-1 防止 tau 蛋白病变。我们 假设 XBP-1 的靶基因可以调节病理性 tau 蛋白的积累和清除。 为了验证这一假设，我们在没有 ER 应激的情况下上调了神经元中的 UPR，使用 表达转基因的组成型活性 XBP-1。该系统的转录组学研究 揭示了调节 tau 蛋白病并与其他调控相互作用的关键 XBP-1 靶基因 UPR 分支机构（ATF6 和 PERK 分支机构）。鉴于普遍定期审议的高度保护 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 剖析 UPR 防止 tau 神经毒性的机制。具体目标 该项目的目的是： 1) 确定 XBP1 介导的抑制的分子机制 tau蛋白病； 2) 检查 UPR 分支串扰对 tau 清除和相关 ER 的贡献 退化，3) 解决 XBP-1 靶基因与神经退行性疾病的疾病相关性 tau蛋白病的人类疾病和小鼠模型。按计划完成该项目将 了解 UPR 参与 tau 蛋白病变的分子机制。我们还将探索 XBP-1s 介导的哺乳动物大脑中 tau 清除的神经保护翻译潜力。