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: 10551219
• 负责人: Brian C. Kraemer
• 金额: $ 52万
• 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/10551219
• 关键词: ATF6 gene; Address; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Animal Model; Animals; Bioinformatics; Brain; Caenorhabditis elegans; Cellular Stress; Cessation of life; Dementia; Deposition; Diagnostic; Disease; Disease model; Drug Metabolic Detoxication; Endoplasmic Reticulum; 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; transgene expression; translational potential; 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.

病理沉积异常聚集的tau蛋白在神经元是诊断之一