The role of glia in monitoring neuronal proteostasis in aging

尽管脑中的非神经细胞神经胶质细胞越来越多地与衰老和神经退行性疾病有关，但我们对这些细胞在衰老过程中如何与神经元相互作用知之甚少。神经退行性疾病，如阿尔茨海默病，其特征是聚集的错误折叠的蛋白质，这可能导致细胞死亡和功能障碍。细胞已经开发出系统，以细胞隔间特有的方式检测和修复这些问题；然而，随着生物体年龄的增长，这些对蛋白质错误折叠的反应开始失效。我们此前已经证明，当神经元经历蛋白质毒性和压力时，它们会发出信号向其他细胞发出警报，这可能是人体如何自然修复神经退行性疾病中蛋白质错误折叠的线索。然而，还没有人研究细胞胞浆中的胶质细胞如何对蛋白质应激做出反应。我们的实验室以前发现，胞浆未折叠蛋白反应的主要调节因子热休克因子1(HSF-1)的神经元过度表达能够向远端细胞发出信号，增加健康的蛋白质折叠效应器，帮助生物体活得更长。在这里，我们提出，神经胶质细胞也可以发出热休克反应的信号，以协调泛有机体的反应并延长寿命(目标1)。在这个目标上，我们的方法利用模式生物线虫的遗传可控性、短寿命和简单的成像，来研究衰老过程中组织之间的非细胞自主信号。为了进一步说明胶质细胞在将神经元从蛋白质毒性中拯救出来的作用，我们将研究哺乳动物大脑中的小胶质细胞。在这里，我们询问健康的小胶质细胞是否能够拯救受到tau蛋白错误折叠的神经元，这是阿尔茨海默病和其他痴呆的常见特征，以及老化的小胶质细胞是否可能在帮助神经元方面存在缺陷。我们将评估小胶质细胞如何监测神经元的内部蛋白质稳态(目标2)。为了做到这一点，我们将利用转录组分析、可诱导的小鼠疾病模型和快速改进的细胞培养方法。通过这一提议产生的数据将为大脑如何处理蛋白质应激提供新的线索，并将确定神经胶质细胞的新信号机制，这将提高我们对神经退行性疾病病理的理解。

Although glia, the non-neuronal cells of the brain, are increasingly implicated in aging and neurodegenerative disease, we know very little about how these cells interact with neurons during aging. Neurodegenerative diseases, like Alzheimer's disease, are characterized by aggregated misfolded proteins, which can cause cell death and dysfunction. Cells have developed systems to detect and fix these problems in a cellular compartment-specific manner; however, these responses to protein misfolding start to fail as organisms age. We have previously shown that neurons send out signals to alert other cells when they experience protein toxicity and stress, which could be a clue towards how the body could naturally fix protein misfolding in neurodegenerative disease. However, no one has yet investigated how glia respond to protein stress in the cytosolic compartment of the cell. Our laboratory previously showed that neuronal over-expression of the main regulator of the cytosolic unfolded protein response, heat shock factor 1 (HSF-1), is able to signal to distal cells to increase healthy protein folding effectors and help organisms live longer. Here, we propose that glial cells can also signal the heat shock response to coordinate a pan-organismal response and promote longevity (Aim 1). Our approach in this aim takes advantage of the genetic tractability, short lifespan, and simple imaging of the model organism, C. elegans, to study non-cell autonomous signaling between tissues in aging. To further address the role of glia in rescuing neurons from protein toxicity, we will examine microglia in the mammalian brain. Here, we ask whether healthy microglia can rescue neurons stressed with tau protein misfolding, which is a common feature of Alzheimer's disease and other dementias, and whether aged microglia might be defective in their aid to neurons. We will assess how microglia surveil the internal protein homeostasis of neurons (Aim 2). To do this, we will take advantage of transcriptome analysis, inducible mouse disease models, and rapidly improving cell culture methods. Data generated through this proposal will shed new light on how the brain deals with protein stress and will identify novel signaling mechanisms of glial cells that will improve our understanding of neurodegenerative disease pathology.