Glial regulation of longevity through a transcellular unfolded protein response

细胞反复暴露在破坏蛋白质稳态的各种应激源中(例如感染， 过量营养、热量、基因突变)，导致蛋白质错误折叠和聚集。保持蛋白质含量 动态平衡(蛋白质平衡)，细胞进化出特定的应激反应，如未折叠的 内质网的蛋白质反应(UPRER)。在内质网压力的时候，当错误折叠或 未折叠的蛋白质压倒了内质网，UPRER被启动以恢复蛋白平衡。 不幸的是，随着年龄的增长，建立有效的UPRER的能力会受到损害，这可能是导致 错误折叠的蛋白质堆积--这是衰老和许多退行性疾病的中心分子标志。 我们的实验室发现，UPRER转录因子XBP-1s在神经元中的异位表达充足 以防止UPRER在整个生物体中的年龄损失。令人惊讶的是，XBP-1S导联的神经元表达 对远端肠道细胞中UPRER的非自主激活，延长线虫的寿命。 最初，这种现象只被归因于神经元，然而我们实验室最近的数据表明，神经胶质细胞 细胞是更强大的细胞，非自主调节内质网的应激和寿命。动物缺乏一种 神经胶质细胞亚型对慢性内质网应激更敏感。相反，在胶质细胞中表达XBP-1s会导致 强健的内质网应激抵抗和寿命延长，其机制与神经元启动的机制不同 XBP-1S。因此，我们假设神经胶质细胞在协调组织内质网应激中起核心作用。 抵抗力和长寿。在这项提议中，我们概述了我们的战略，以查明神经胶质的起源和身份 细胞非自主信号(目标1)，并揭示信号在远端被感知的机制 组织(目标2)。我们的方法利用了结合了使用线虫的传统优势的技术 作为模型系统(遗传可操纵性、透明度、寿命短)，采用先进技术(大颗粒 流式细胞术和组织特异性核糖体图谱)研究组织之间的细胞非自主信号 在老龄化的背景下。通过这项提议产生的数据将牵涉到神经胶质细胞作为非自治细胞 调节衰老，为新陈代谢和神经退行性疾病治疗开辟新的途径。

Cells are repeatedly exposed to various stressors that disrupt protein homeostasis (such as infection, excess nutrients, heat, genetic mutations), resulting in protein misfolding and aggregation. To maintain protein homeostasis (proteostasis), cells have evolved compartment specific stress responses such as the Unfolded Protein Response of the endoplasmic reticulum (UPRER). In times of ER stress when the load of misfolded or unfolded proteins overwhelms the ER, the UPRER is initiated to restore proteostasis. Unfortunately, the ability to mount an effective UPRER is impaired with age, which likely contributes to the accumulation of misfolded proteins - a central molecular hallmark of aging and many degenerative diseases. Our laboratory discovered that ectopic expression of the UPRER transcription factor xbp-1s in neurons is sufficient to prevent age-onset loss of UPRER throughout the organism. Surprisingly, neuronal expression of xbp-1s leads to cell non-autonomous activation of the UPRER in distal, intestinal cells and extends lifespan in C. elegans. Initially this phenomenon was ascribed only to neurons, however recent data from our lab suggests glial cells are more potent cell non-autonomous regulators of ER stress resistance and longevity. Animals lacking a subtype of glial cell are more susceptible to chronic ER stress. Conversely, expressing xbp-1s in glia results in robust ER stress resistance and lifespan extension in a mechanism that is distinct from that initiated by neuronal xbp-1s. Therefore, we hypothesize that glial cells play a central role in coordinating organismal ER stress resistance and longevity. In this proposal, we outline our strategy to pinpoint the origin and identity of the glial cell non-autonomous signal (Aim 1) and to uncover the mechanism by which the signal is perceived in distal tissues (Aim 2). Our approach utilizes techniques which combine the traditional advantages of using C. elegans as a model system (genetic tractability, transparency, short lifespan), with advanced technologies (large particle flow cytometry and tissue-specific ribosomal profiling) to study cell non-autonomous signaling between tissues in the context of aging. Data generated through this proposal will implicate glia as cell non-autonomous regulators of aging and open new avenues for metabolic and neurodegenerative disease therapeutics.