Proteostasis in Aging and Neurodegenerative Disease

衰老和神经退行性疾病中的蛋白质稳态

• 批准号: 10183109
• 负责人: RICHARD I MORIMOTO
• 金额: $ 290.76万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 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/10183109
• 关键词: Address; Affect; Age; Aging; Alzheimer' 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 TDP-43; 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

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.

项目摘要 社会面临的最具挑战性的问题之一是， 伴随着神经退行性疾病的风险增加。该提案的中心主题是 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，并导致细胞和组织衰竭和神经变性疾病。在这 PPG，我们已经组建了S队。Finkbeiner（UCSF），D. Finley（哈佛），J. Frydman（斯坦福大学），J. Kelly（Scripps）和R. Morimoto（西北大学）研究了衰老中蛋白质稳态的失败， 阿尔茨海默病（AD）、ALS、亨廷顿舞蹈病（HD）中Tau、SOD 1和扩增polyQ的错误折叠和聚集 疾病和共济失调。PPG团队的一个独特优势是我们的专业知识， 包括S.酿酒酵母C.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的多种实验方法，聚集的活细胞成像 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，运输机制，以及 PN由泛素-蛋白酶体和自噬溶酶体途径组成。了解如何 衰老在细胞、组织和生物体水平上影响PN，这将为我们提供一个关于 蛋白质稳态失败期间的事件，其有助于并加速Tau、SOD 1和 扩增的polyQ蛋白导致AD和其他神经退行性疾病。通过四个项目， 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，以影响新生的， 链合成和Tau和聚谷氨酰胺在酵母中的非途径聚集特性（Proj. 1)和 短寿命和长寿命C. elegans（Proj. 4）。我们将检查PN的降解臂 在蛋白酶体活性水平改变的转基因小鼠中以及Tau和突变体对蛋白毒性的影响 SOD 1（项目2），并在人iPSC衍生的患者神经元中，通过监测自噬性溶酶体 路径（Proj。3)受到老化和Tau或TDP 43表达的挑战。这些项目将得到以下方面的支持： 协调管理核心A，蛋白质稳态传感器核心B，其开发PN报告基因以定量 不同PN活性、蛋白质稳态蛋白质组学核心C和蛋白质稳态调节剂药理学核心D 开发一种小分子策略，以恢复衰老和神经退行性疾病中的PN功能。 通过合作，核心和项目将产生PN试剂和工具，数据集和小分子 量化和扰动PN的不同成分，生成老化的比较分析， 神经退行性疾病，并开发一种小分子策略来预防或 逆转PN中导致神经退行性疾病的年龄和疾病依赖性失效。