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

项目摘要 越来越多的证据表明，安装有效的Nrf2介导的基因的能力 在衰老过程中，对氧化应激的表达反应下降。尤其是核能 但不是胞浆Nrf2在AD患者的神经元中被耗尽。在动物模型中，Nrf2的丢失 信号会加剧淀粉样蛋白和tau的沉积，神经炎症和认知障碍， 而Nrf2信号的诱导对这些表型具有保护作用。而有毒的牛磺酸 组装、氧化应激、细胞骨架破坏和自噬缺陷是主要特征。 包括阿尔茨海默病，这些细胞脑表型是如何在分子水平上整合的 在tau发病过程中是否产生生理或病理反应尚不清楚。在……里面 除了已知的SSH1对细胞骨架、线粒体和自噬的调节外，我们的 新的初步研究表明，SSH1途径与Nrf2相交，以抑制和滴定 NRF2信令。我们的总体假设是SSH1和NRF2之间的联系 通路代表了一个临界点，它打破了退化和保护之间的平衡 在蛋白毒性和氧化应激期间。因为NRF2和SSH1都是在 氧化应激，了解Nrf2和SSH1之间的联系是如何生理和 病理调控将为治疗AD和其他肌萎缩侧索硬化症提供关键的见解。 利用体外重组蛋白、细胞模型、动物模型和死后脑 结合机械性生化、免疫化学、原位邻近连接分析、RNA- SEQ和蛋白质组学研究，我们将定义和剖析SSH1-Nrf2联系如何改变平衡 神经退行性变与神经保护之间的关系。

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.