Nrf1-dependent Proteotoxic Stress Response

Nrf1 依赖性蛋白毒性应激反应

• 批准号: 10121370
• 负责人: Senthil Kumar Radhakrishnan
• 金额: $ 18.11万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10121370
• 关键词: Aging; Alzheimer' s Disease; Autophagocytosis; Cells; Data; Defect; Degradation Pathway; Dementia; Development; Disease; Future; Genes; Genetic Transcription; Impaired cognition; Lead; Mediating; Memory Loss; Molecular; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Operating System; Pathologic; Pathway interactions; Process; Proteasome Inhibitor; Proteins; Quality Control; Recovery; Role; Route; Stress; System; Ubiquitin; age related; arm; biological adaptation to stress; cerebral atrophy; functional decline; hyperphosphorylated tau; multicatalytic endopeptidase complex; neuron loss; novel strategies; protein aggregation; protein degradation; proteotoxicity; response; tau Proteins; therapeutic target; transcription factor

ABSTRACT Alzheimer's disease (AD) is the most common cause of age-related dementia characterized by memory loss and cognitive decline. One of the pathological hallmarks of AD at the molecular level is the presence of neurofibrillary tangles composed of aggregates of hyperphosphorylated tau in the neurons leading to 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. Given that tau can be degraded by the proteasome as well as the autophagy-lysosomal network, possible defects in one or both of these catabolic pathways could explain its accumulation in the diseased neurons. Consistent with this notion, accumulating evidence points to a progressive decline in the function of both the proteasome and the autophagy-lysosomal network during the aging process. Therefore, it is important to understand how these protein clearance systems operate in cells of neuronal origin and elucidate how these cells handle proteotoxic stress. Our previous studies have established the transcription factor Nrf1as a key player in responding to cellular proteotoxic stress. Nrf1, by its ability to induce de novo synthesis of proteasome subunit genes in response to proteasome inhibitors, promotes the recovery of proteasome activity, thus mitigating proteotoxic stress and enhancing cellular survival. Interestingly, our preliminary data indicate that under similar circumstances, Nrf1 can also transcriptionally upregulate multiple components of the autophagy pathway, and thus could offer the cells an additional route to cope with proteotoxic stress. Here we propose to investigate this phenomenon further in cells of neuronal origin that are relevant to AD. If successful, our studies could cement the role of Nrf1 as a master transcription factor that controls the two major arms of the cellular protein quality control pathways – the ubiquitin-proteasome system, and autophagy in neuronal cells. This could lead to future studies aimed at the development of novel strategies to enhance these protein degradation pathways to mediate tau clearance and alleviate proteotoxic stress in the AD neurons.

摘要 阿尔茨海默病（AD）是年龄相关性痴呆的最常见原因 以记忆丧失和认知能力下降为特征。一个病理学特征是 AD在分子水平上的一个重要特征是存在神经元缠结， 神经元中过度磷酸化tau的聚集导致严重的蛋白毒性 这些细胞的压力。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的显著病理特征。考虑到tau可以 被蛋白酶体以及自噬-溶酶体网络降解，可能 这些分解代谢途径中的一个或两个的缺陷可以解释它在细胞中的积累。 患病的神经元与这一观点相一致，越来越多的证据表明， 蛋白酶体和自噬-溶酶体功能的进行性下降 网络在老化过程中因此，重要的是要了解这些 蛋白质清除系统在神经元来源的细胞中起作用，并阐明这些系统如何在神经元来源的细胞中起作用。 细胞处理蛋白毒性应激。我们之前的研究已经建立了转录 Nrf 1因子在细胞蛋白毒性应激反应中起关键作用。nrf 1通过它的能力 诱导蛋白酶体亚单位基因的从头合成，以响应蛋白酶体 抑制剂，促进蛋白酶体活性的恢复，从而减轻蛋白毒性 应激和增强细胞存活。有趣的是，我们的初步数据表明， 在类似的情况下，Nrf 1也可以转录上调多个 自噬途径的组成部分，因此可以为细胞提供额外的途径 来科普蛋白毒性压力在这里，我们建议进一步研究这一现象 在与AD相关的神经元起源的细胞中。如果成功，我们的研究可以 巩固Nrf 1作为控制两个主要臂的主转录因子的作用 细胞蛋白质质量控制途径-泛素-蛋白酶体系统， 神经细胞的自噬。这可能会导致未来的研究，旨在发展 新的策略来增强这些蛋白质降解途径， 清除并减轻AD神经元中的蛋白毒性应激。