Nrf1-dependent Proteotoxic Stress Response

摘要 阿尔茨海默病(AD)是导致老年性痴呆的最常见原因 以记忆力减退和认知衰退为特征。病理特征之一是 阿尔茨海默病在分子水平上的存在是由神经纤维缠结组成的 过度磷酸化的tau在神经元中聚集，导致严重的蛋白毒性 这些细胞中的压力。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一个显著病理特征。考虑到tau可以 可能被蛋白酶体和自噬-溶酶体网络降解 这些分解代谢途径中的一个或两个的缺陷可以解释它在 有病的神经元。与这个概念一致的是，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 在老化过程中的网络。因此，重要的是要了解这些 蛋白质清除系统在神经元起源的细胞中运行，并阐明这些 细胞可以应对蛋白毒性压力。我们之前的研究已经建立了转录 Nrf1因子在细胞蛋白毒性应激反应中起关键作用。NRF1，根据其能力 诱导蛋白酶体亚单位基因从头合成反应蛋白酶体 抑制剂，促进蛋白酶体活性的恢复，从而减轻蛋白毒性 压力和提高细胞存活率。有趣的是，我们的初步数据显示 在类似的情况下，Nrf1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一条额外的途径 以应对蛋白毒性压力。在这里，我们建议进一步研究这一现象 在与阿尔茨海默病相关的神经元起源的细胞中。如果成功，我们的研究可能会 巩固Nrf1作为控制两大臂的主要转录因子的作用 细胞蛋白质质量控制途径-泛素-蛋白酶体系统，以及 神经细胞的自噬。这可能会导致未来针对这一发展的研究 增强这些蛋白质降解途径以调节tau的新策略 清除和减轻AD神经元中的蛋白毒性应激。

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.