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tau蛋白异常的病理沉积是诊断之一 阿尔茨海默氏病（AD）和相关痴呆（ADRD）的标志。病理学如何导致 神经元的功能障碍和变性仍然是一个谜。但是，神经元功能障碍和 神经变性显然会引起痴呆。了解异常tau如何贡献 AD和ADRD中的神经变性，我们在秀丽隐杆线虫中建立了一个转基因模型 由人tau聚集驱动的神经变性。在以前的工作中，我们确定了XBP-1， 展开蛋白质反应（UPR）的主要转录调节剂，作为关键调节剂 病理tau积累和毒性。 ER压力和UPR的激活显然已经存在 尽管功能后果，其他实验室与其他实验室有关 tau病理学上的UPR激活尚不清楚。我们利用了我们的秀丽隐杆线虫模型 tauopathy剖析UPR在tau病理学中的功能作用。我们发现Tau病理学 可以诱导ER应力，并且UPR激活通过XBP-1预防tauopathy。我们 假设XBP-1S靶基因可以调节病理tau的积累和清除。 为了检验这一假设，我们使用a，在没有ER应力的情况下，我们上调了神经元中的UPR 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tauopathy并与其他调节的关键XBP-1S靶基因 UPR的分支（ATF6和PERK分支）。考虑到UPR的高水平 哺乳动物和秀丽隐杆线虫之间的系统，我们建议利用现有模型，然后转基因 解剖UPR预防TAU神经毒性的机制。具体目的 该项目是：1）确定XBP1S介导的抑制的分子机制 tauopathy; 2）检查有助于tau间隙和与ER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 人类疾病和小鼠模型。按建议的项目完成项目 告知UPR参与tauopathy的分子机制。我们还将探索 XBP-1S介导的TAU清除率在哺乳动物大脑中的神经保护性转化潜力。