Analysis of Nrf1 pathway in Alzheimer's Disease

阿尔茨海默病 Nrf1 通路分析

• 批准号: 10288256
• 负责人: Senthil Kumar Radhakrishnan
• 金额: $ 31.05万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10288256
• 关键词: Aging; Alzheimer' s Disease; Alzheimer' s disease model; Autophagocytosis; Biological Assay; CRISPR screen; Cell Line; Cells; Data; Defect; Degradation Pathway; Development; Disease; Doxycycline; Erythroid; Future; Genes; Genetic Screening; Genetic Transcription; Impaired cognition; Lead; Mediating; Memory Loss; Molecular; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Nuclear; Operating System; Pathologic; Pathway interactions; Phosphotransferases; Process; Proteasome Inhibition; Proteins; Quality Control; Recovery; Role; Route; Shapes; Stress; Testing; Work; base; cerebral atrophy; druggable target; experience; functional decline; functional status; hyperphosphorylated tau; loss of function; multicatalytic endopeptidase complex; neuron loss; novel strategies; novel therapeutics; overexpression; protein aggregation; protein degradation; proteotoxicity; response; tau Proteins; tau aggregation; therapeutic target; transcription factor

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.

阿尔茨海默病（AD）是一种进行性神经退行性疾病， 以认知能力下降和记忆丧失为特征。一个典型的病理学 AD在分子水平上的标志是神经元缠结的存在 由神经元中过度磷酸化的tau蛋白聚集体组成。这些聚集体 对神经元蛋白质质量控制途径造成严重负担， 严重的蛋白毒性应激。持续的蛋白毒性应激通常导致 神经元细胞死亡最终导致脑萎缩，这是AD的一个突出病理特征。 我们以前的工作已经牢固地确立了转录因子Nrf1作为一个核心球员 对细胞蛋白毒性应激的反应。Nrf1通过其诱导新生的能力 响应蛋白酶体抑制的蛋白酶体亚单位基因的合成，促进 蛋白酶体活性的恢复，从而减轻蛋白毒性应激并增强 细胞存活然而，无论Nrf1通路在AD神经元中是否活跃， 目前尚不清楚是否存在蛋白毒性应激。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 功能丧失的遗传筛选，我们建议发现激酶，可以作为 Nrf1通路的负调节因子。如果成功，我们的研究可以帮助阐明 Nrf1通路在受AD折磨的神经元细胞中的作用，并为未来的研究奠定基础。 旨在开发新疗法以促进神经元蛋白质降解的研究 途径，以使tau清除，从而减轻蛋白毒性应激。