Proteostasis in Aging and Neurodegenerative Disease

衰老和神经退行性疾病中的蛋白质稳态

基本信息

批准号：
9788203
负责人：
RICHARD I MORIMOTO
金额：
$ 253.41万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9788203
关键词：
Address Affect Age Aging Alzheimer&apos s Disease Amyloid beta-Protein Ataxia Autophagocytosis Biochemical Biological Models Biology Biophysics Brain Caenorhabditis elegans Cell Differentiation process Cells Chemicals Communication Data Set Defect Development Disease Disease model Dose Ensure Event Exposure to Failure Functional disorder GRN gene Genes Genetic Goals Health Human Huntington Disease Huntington gene Individual Intestines Link Lipids Longevity Lysosomes Measures Modeling Molecular Molecular Chaperones Monitor Motor Neurons Mus Muscle Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Nucleosome Core Particle Organelles Organism PGRN gene Pathology Pathway interactions Patients Pharmacodynamics Pharmacology Phenotype Physiological Prevention Property Protein Biosynthesis Proteins Proteomics Quality Control Reagent Regulation Reporter Research Personnel Resistance Risk Role Saccharomyces cerevisiae Secure Signal Pathway Signal Transduction Societies Solubility Stress Tauopathies Techniques Testing Tissues Toxic effect Training Transgenic Mice Ubiquitin Yeasts age effect age related aggregation pathway arm biological systems cell type comparative data sharing genetic approach high throughput screening in vivo induced pluripotent stem cell insight live cell imaging misfolded protein mouse model multicatalytic endopeptidase complex mutant novel particle polyglutamine prevent protein aggregation protein degradation protein folding protein misfolding proteostasis proteotoxicity response sensor small molecule superoxide dismutase 1 synuclein tau Proteins tau aggregation tau expression technology development tissue culture tool transcriptomics

项目摘要

Project Summary One of the most challenging problems facing society is the mixed benefit of longer lifespan that is also accompanied by the increased risk for neurodegenerative diseases. A central theme of this proposal is that aging is associated with the declining capability of the protein quality control machinery, leading to protein misfolding and aggregation, and resulting in cell and tissue failure and neurodegenerative disease. In this PPG, we have assembled the team of S. Finkbeiner (UCSF), D. Finley (Harvard), J. Frydman (Stanford), J. Kelly (Scripps) and R. Morimoto (Northwestern) to examine proteostasis failure in aging as the basis for misfolding and aggregation of Tau, SOD1 and expanded polyQ in Alzheimer's disease (AD), ALS, Huntington's disease and Ataxias, respectively. A distinctive strength of this PPG team is our expertise with multiple biological systems including S. cerevisiae, C. elegans, mice, patient derived cells and differentiated neurons, and multiple experimental approaches from biochemical and biophysical, live cellular imaging of aggregation phenotypes, and small molecule high-throughput screens. We posit that the unique richness of approaches afforded by this team will provide novel insights that will uncover how aging affects the proteostasis network (PN) of protein synthesis and molecular chaperones, transport machineries, and the degradative arms of the PN comprised of the ubiquitin-proteasome and autophagy lysosomal pathways. An understanding of how aging affects the PN at the cellular, tissue, and organismal level will provide a mechanistic understanding on the events during proteostasis failure that contributes to and accelerates aggregation of Tau, SOD1 and expanded polyQ proteins leading to AD and other neurodegenerative diseases. Through four Projects and four Cores, our team will explore how aging affects the function of molecular chaperones to influence nascent- chain synthesis and the off-pathway aggregation properties of Tau and polyglutamine in yeast (Proj. 1) and in different tissues of short-and-long-lived C. elegans (Proj. 4). We will examine the degradative arms of the PN in transgenic mice with altered levels of proteasome activity and the effects on proteotoxicity of Tau and mutant SOD1 (Proj. 2), and in human iPSCs derived patient neurons by monitoring the autophagic lysosomal pathways (Proj. 3) challenged by aging and expression of Tau or TDP43. These Projects will be supported by: the coordinating Administrative Core A, Proteostasis Sensors Core B that develops PN reporters to quantify different PN activities, Proteostasis Proteomics Core C, and the Proteostasis Regulator Pharmacology Core D to develop a small molecule strategy to restore PN functionality in aging and neurodegenerative disease. Working together, the Cores and Projects will generate PN reagents and tools, datasets and small molecules to quantify and perturb different components of the PN, to generate a comparative analysis of aging and neurodegeneration across all biological systems, and to develop a small molecule strategy to prevent or reverse the age-and-disease dependent failures in the PN leading to neurodegenerative disease.

项目概要社会面临的最具挑战性的问题之一是延长寿命的混合效益，这也是伴随着神经退行性疾病风险的增加。该提案的一个中心主题是衰老与蛋白质质量控制机制的能力下降有关，导致蛋白质错误折叠和聚集，导致细胞和组织衰竭和神经退行性疾病。在这个 PPG，我们组建了S. Finkbeiner（加州大学旧金山分校）、D. Finley（哈佛大学）、J. Frydman（斯坦福大学）、J. Frydman（斯坦福大学）等团队。 Kelly（斯克里普斯）和 R. Morimoto（西北大学）研究了衰老过程中蛋白质稳态失灵的基础阿尔茨海默病 (AD)、ALS、亨廷顿舞蹈症中 Tau、SOD1 和扩展的 PolyQ 的错误折叠和聚集分别是疾病和共济失调。 PPG 团队的独特优势是我们在多个方面的专业知识生物系统，包括酿酒酵母、线虫、小鼠、患者来源的细胞和分化的神经元，以及来自生物化学和生物物理、聚集的活细胞成像的多种实验方法表型和小分子高通量筛选。我们认为方法的独特丰富性该团队提供的研究将提供新颖的见解，揭示衰老如何影响蛋白质稳态网络 (PN) 蛋白质合成和分子伴侣、运输机械以及降解臂 PN 由泛素蛋白酶体和自噬溶酶体途径组成。了解如何衰老会在细胞、组织和有机体水平上影响 PN，这将为我们提供机制上的理解蛋白质稳态失败过程中导致并加速 Tau、SOD1 和扩展的polyQ蛋白会导致AD和其他神经退行性疾病。通过四个项目和四个核心，我们的团队将探索衰老如何影响分子伴侣的功能，从而影响新生- 酵母（Proj. 1）和酵母中 Tau 和聚谷氨酰胺的链合成和非途径聚集特性短寿命和长寿命线虫的不同组织（Proj. 4）。我们将检查 PN 的退化武器在蛋白酶体活性水平改变的转基因小鼠中以及对 Tau 和突变体蛋白毒性的影响 SOD1 (Proj. 2)，以及通过监测自噬溶酶体在人类 iPSC 衍生的患者神经元中受到衰老和 Tau 或 TDP43 表达挑战的途径（项目 3）。这些项目将得到以下机构的支持：协调管理核心 A、蛋白质稳态传感器核心 B，开发 PN 记者以进行量化不同的 PN 活性、蛋白质稳态蛋白质组学核心 C 和蛋白质稳态调节药理学核心 D 开发一种小分子策略来恢复衰老和神经退行性疾病中的 PN 功能。核心和项目共同工作将生成 PN 试剂和工具、数据集和小分子量化和扰动 PN 的不同组成部分，生成老化和老化的比较分析跨所有生物系统的神经变性，并开发小分子策略来预防或逆转因年龄和疾病导致的 PN 衰竭，从而导致神经退行性疾病。