The role of glia in monitoring neuronal proteostasis in aging

神经胶质细胞在监测衰老过程中神经元蛋白质稳态中的作用

基本信息

批准号：
10250348
负责人：
Holly Katherine Gildea
金额：
$ 4.24万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10250348
关键词：
Acute Address Age Aging Alzheimer&apos s Disease Animal Model Brain Caenorhabditis elegans Cell Compartmentation Cell Culture Techniques Cell Death Cells Cessation of life Chronic Coculture Techniques Cytosol Data Data Set Dementia Development Disease Disease model Distal Event Failure Functional disorder Gene Expression Profile Genes Genetic Health Heat Stress Disorders Heat shock proteins Heat-Shock Response Homeostasis Human Image Immune response Inflammation Interneurons Laboratories Lead Light Link Longevity Maps Measures Mediating Metabolic Methods Microglia Modeling Molecular Chaperones Monitor Mus Mutagenesis Nerve Degeneration Nervous system structure Neurodegenerative Disorders Neuroglia Neurons Organism Oxidative Stress Pathway Pathology Pathway interactions Peripheral Phenotype Proteins Receptor Signaling Reporter Role Sampling Signal Pathway Signal Transduction Stains Stress Synapses System Tauopathies Testing Tissues Toxic effect Work age related aged biological adaptation to stress brain cell cell injury connectome disease phenotype experience healthspan healthy aging heat shock transcription factor heat-shock factor 1 improved in vivo insight misfolded protein mouse model mutant neuroinflammation neuronal circuitry neuronal survival neurotoxic neurotransmission normal aging novel overexpression programs protein aggregation protein folding protein function protein misfolding proteostasis proteotoxicity response tau Proteins tau aggregation tau mutation tau phosphorylation transcriptome transcriptome sequencing

项目摘要

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.

尽管神经胶质是大脑的非神经元细胞，它越来越涉及衰老和神经退行性疾病，但我们对这些细胞在衰老过程中如何与神经元相互作用一无所知。神经退行性疾病，例如阿尔茨海默氏病，其特征是综合蛋白质的综合蛋白质，可能导致细胞死亡和功能障碍。细胞已经开发了以细胞室特异性方式检测和解决这些问题的系统。但是，随着生物的年龄，这些对蛋白质错误折叠的反应开始失败。我们以前已经表明，神经元在经历蛋白质毒性和胁迫时发出信号来提醒它们，这可能是对人体如何自然固定神经退行性疾病中蛋白质错误折叠的线索。但是，尚无人研究细胞胞质室中的胶质应对蛋白质应激的反应。我们的实验室先前表明，胞质展开的蛋白质反应的主要调节剂的神经元过表达热休克因子1（HSF-1）能够向远端细胞发出信号以增加健康的蛋白质折叠效应子并帮助生物寿命更长。在这里，我们建议神经胶质细胞还可以向热激反应发出以辅助泛抗反应并促进寿命（AIM 1）。我们在此目的中的方法利用了模型有机体的遗传障碍性，短寿命和简单的成像，以研究衰老中组织之间的非细胞自主信号传导。为了进一步解决神经胶质在蛋白质毒性中挽救神经元的作用，我们将检查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挽救tau蛋白错误折叠压力的神经元，这是阿尔茨海默氏病和其他痴呆症的常见特征，以及老化的小胶质细胞对神经元有助于有缺陷。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（AIM 2）。为此，我们将利用转录组分析，诱导小鼠疾病模型以及快速改善细胞培养方法。通过该提案产生的数据将为大脑如何处理蛋白质应激提供新的启示，并将确定神经胶质细胞的新信号传导机制，这将改善我们对神经退行性疾病病理学的理解。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

IGI-LuNER: single-well multiplexed RT-qPCR test for SARS-CoV-2.

DOI：
10.1101/2020.12.10.20247338
发表时间：
2020-12-11
期刊：
medRxiv : the preprint server for health sciences
影响因子：
0
作者：
Stahl, Elizabeth C;Tsuchida, Connor A;Doudna, Jennifer A
通讯作者：
Doudna, Jennifer A

Robotic RNA extraction for SARS-CoV-2 surveillance using saliva samples.

DOI：
10.1371/journal.pone.0255690
发表时间：
2021
期刊：
PloS one
影响因子：
3.7
作者：
Hamilton JR;Stahl EC;Tsuchida CA;Lin-Shiao E;Tsui CK;Pestal K;Gildea HK;Witkowsky LB;Moehle EA;McDevitt SL;McElroy M;Keller A;Sylvain I;Hirsh A;Ciling A;Ehrenberg AJ;Ringeisen BR;Huberty G;Urnov FD;Giannikopoulos P;Doudna JA;IGI SARS-CoV-2 Consortium
通讯作者：
IGI SARS-CoV-2 Consortium