The role of glia in monitoring neuronal proteostasis in aging

尽管神经胶质细胞（大脑的非神经元细胞）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。细胞已经发展出以细胞区室特异性方式检测和解决这些问题的系统；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。我们之前已经证明，当神经元经历蛋白质毒性和压力时，它们会发出信号来警告其他细胞，这可能是身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，还没有人研究过胶质细胞如何对细胞胞质室中的蛋白质应激作出反应。我们的实验室先前表明，胞质未折叠蛋白反应的主要调节因子热休克因子1 （HSF-1）的神经元过表达能够向远端细胞发出信号，以增加健康的蛋白折叠效应，并帮助生物体延长寿命。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，以协调泛生物反应并促进寿命（Aim 1）。我们的研究方法利用了模式生物秀丽隐杆线虫的遗传易变性、短寿命和简单成像的优势，来研究衰老过程中组织间的非细胞自主信号传导。为了进一步探讨神经胶质细胞在拯救神经元免受蛋白质毒性中的作用，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可以拯救tau蛋白错误折叠的神经元，这是阿尔茨海默病和其他痴呆症的共同特征，以及衰老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内部蛋白质稳态（目的2）。为此，我们将利用转录组分析、诱导小鼠疾病模型和快速改进的细胞培养方法。通过这项提议产生的数据将揭示大脑如何处理蛋白质应激，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学的理解。

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.