Analysis of Nrf1 pathway in Alzheimer's Disease

阿尔茨海默病(AD)是一种进行性神经退行性疾病， 以认知衰退和记忆丧失为特征的。最具代表性的病理性疾病之一 阿尔茨海默病分子水平的特征是神经原纤维缠结的存在 由神经元中过度磷酸化的tau聚集体组成。这些集合体 对神经元蛋白质质量控制途径施加严重负担，导致 这些细胞中存在严重的蛋白毒性应激。持续的蛋白毒性应激通常会导致 神经细胞死亡最终导致脑萎缩，这是阿尔茨海默病的显著病理特征。 我们之前的工作已经牢固地确立了转录因子Nrf1作为核心角色 在对细胞蛋白毒性应激的反应中。NRF1，通过其诱导从头开始的能力 蛋白酶体抑制促进蛋白酶体亚单位基因的合成 蛋白酶体活性的恢复，从而缓解蛋白毒性应激，增强 细胞存活。然而，无论Nrf1通路在AD神经元中是否活跃 经历蛋白毒性应激目前尚不清楚。使用基于细胞系的AD模型， 在这里，我们建议询问Nrf1通路的功能状态。此外，使用 在功能丧失的基因筛查中，我们建议发现一种可以作为 Nrf1途径的负调控因子S。如果成功，我们的研究将有助于阐明 Nrf1通路在阿尔茨海默病神经细胞中的作用及为未来奠定基础 旨在开发促进神经元蛋白质降解的新疗法的研究 清除tau的途径，从而减轻蛋白毒性应激。

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is characterized by cognitive decline and memory loss. One of the defining pathological hallmarks of AD at the molecular level is the presence of neurofibrillary tangles composed of aggregates of hyperphosphorylated tau in the neurons. These aggregates impose a severe burden on the neuronal protein quality control pathways resulting in severe proteotoxic stress in these cells. Sustained proteotoxic stress typically results in neuronal cell death culminating in brain atrophy, a prominent pathological feature of AD. Our previous work has firmly established the transcription factor Nrf1 as a central player in responding to cellular proteotoxic stress. Nrf1, by its ability to induce de novo synthesis of proteasome subunit genes in response to proteasome inhibition, promotes the recovery of proteasome activity, thus mitigating proteotoxic stress and enhancing cellular survival. However, whether or not the Nrf1 pathway is active in AD neurons experiencing proteotoxic stress is currently unclear. Using cell line-based models of AD, here we propose to interrogate the functional status of the Nrf1 pathway. Also, using a loss-of-function genetic screen, we propose to uncover kinase(s) that could act as negative regulator(s) of the Nrf1 pathway. If successful, our studies could help elucidate the role of the Nrf1 pathway in AD-afflicted neuronal cells and set the stage for future studies aimed at developing novel therapeutics to boost neuronal protein degradation pathways to enable tau clearance and thereby mitigate proteotoxic stress.