SSH1-Nrf2 nexus in tipping the balance between degeneration and protection in tauopathies.

SSH1-Nrf2 关系打破了 tau蛋白病中退化和保护之间的平衡。

• 批准号: 10605657
• 负责人: David E Kang
• 金额: $ 50.57万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605657
• 关键词: APP-PS1; Actins; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid; Animal Model; Astrocytes; Autophagocytosis; Autopsy; Binding; Binding Sites; Biochemical; Biological Assay; Brain; Cell Fractionation; Cell Nucleus; Cell model; Cells; Cognitive deficits; Cytoskeleton; Defect; Deposition; Equilibrium; Exhibits; F-Actin; Frontotemporal Lobar Degenerations; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Homologous Gene; Human; Impaired cognition; In Situ; In Vitro; Induction of Apoptosis; Knowledge; Lentivirus; Ligation; Mediating; Microfilaments; Mitochondria; Molecular; Mus; Nerve Degeneration; Neurons; Nuclear; Outcome; Oxidative Stress; Pathogenesis; Pathologic; Pathology; Pathway interactions; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Physiological; Process; Protein Dephosphorylation; Proteins; Proteome; Proteomics; Recombinant Proteins; Regulation; Repression; Rod; Severities; Signal Transduction; Synapses; Tauopathies; Testing; Titrations; Transfection; cofilin; cohort; immunoreactivity; insight; mind control; mutant; neuroinflammation; neuroprotection; oxidation; oxidative damage; proteotoxicity; response; sensor; small hairpin RNA; tau Proteins; tau aggregation; transcriptome; transcriptome sequencing; ubiquitin-protein ligase

Project Summary Accumulating evidence indicates that the ability to mount an effective Nrf2-mediated gene expression response to oxidative stress declines during the aging process. In particular, nuclear but not cytoplasmic Nrf2 is depleted in neurons of AD patients. In animal models, loss of Nrf2 signaling exacerbates amyloid and tau deposition, neuroinflammation, and cognitive deficits, whereas induction of Nrf2 signaling protects against these phenotypes. While toxic tau assemblies, oxidative stress, cytoskeletal disruption, and autophagy defects are cardinal features of tauopathies, including AD, how these cellular brain phenotypes integrate at the molecular level to produce physiological or pathological responses during tau pathogenesis is unknown. In addition to the known regulation of the cytoskeleton, mitochondria, and autophagy by SSH1, our new preliminary studies show that the SSH1 pathway intersects with the Nrf2 to inhibit and titrate Nrf2 signaling. Our overarching hypothesis is that the nexus between the SSH1 and Nrf2 pathways represents a tipping point that tips the balance between degeneration and protection during proteotoxic and oxidative stress in tauopathies. As both Nrf2 and SSH1 are activated under oxidative stress, understanding how the nexus between Nrf2 and SSH1 is physiologically and pathologically regulated will provide key insights into treating AD and other tauopathies. Utilizing in vitro recombinant proteins, cellular models, animal models, and postmortem brains combined with mechanistic biochemical, immunochemical, in situ proximity ligation assays, RNA- seq, and proteomics studies, we will define and dissect how the SSH1-Nrf2 nexus tips the balance between neurodegeneration vs. neuroprotection in tauopathies.

项目概要 越来越多的证据表明，安装有效的 Nrf2 介导基因的能力 在衰老过程中，对氧化应激的表达反应下降。特别是核 AD 患者神经元中的 Nrf2 并未被耗尽，但细胞质中的 Nrf2 并未被耗尽。在动物模型中，Nrf2 缺失 信号传导加剧淀粉样蛋白和 tau 沉积、神经炎症和认知缺陷， 而 Nrf2 信号传导的诱导可以防止这些表型。虽然 tau 有毒 组装、氧化应激、细胞骨架破坏和自噬缺陷是主要特征 包括 AD 在内的 tau蛋白病，这些细胞脑表型如何在分子水平上整合 tau蛋白发病机制中产生生理或病理反应的机制尚不清楚。在 除了已知的 SSH1 对细胞骨架、线粒体和自噬的调节之外，我们的 新的初步研究表明SSH1途径与Nrf2交叉抑制和滴定 Nrf2 信号传导。我们的首要假设是 SSH1 和 Nrf2 之间的联系 途径代表了一个临界点，它打破了退化与保护之间的平衡 在tau蛋白病的蛋白毒性和氧化应激期间。由于Nrf2和SSH1都在下面激活 氧化应激，了解 Nrf2 和 SSH1 之间的关系在生理学和 病理调节将为治疗 AD 和其他 tau蛋白病提供重要见解。 利用体外重组蛋白、细胞模型、动物模型和死后大脑 结合机械生化、免疫化学、原位邻近连接测定、RNA- seq 和蛋白质组学研究，我们将定义并剖析 SSH1-Nrf2 连接如何平衡平衡 tau蛋白病中的神经变性与神经保护之间的关系。