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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：
10432026
负责人：
RICHARD I MORIMOTO
金额：
$ 287.76万
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10432026
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 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

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.

项目总结

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Persistent mRNA localization defects and cell death in ALS neurons caused by transient cellular stress.

由短暂的细胞应激引起的 ALS 神经元中持续的 mRNA 定位缺陷和细胞死亡。

DOI：
10.1016/j.celrep.2021.109685
发表时间：
2021
期刊：
Cell reports
影响因子：
8.8
作者：
Markmiller,Sebastian;Sathe,Shashank;Server,KariL;Nguyen,ThaiB;Fulzele,Amit;Cody,Neal;Javaherian,Ashkan;Broski,Sara;Finkbeiner,Steven;Bennett,EricJ;Lécuyer,Eric;Yeo,GeneW
通讯作者：
Yeo,GeneW

Transcriptional signatures in iPSC-derived neurons are reproducible across labs when differentiation protocols are closely matched.

DOI：
10.1016/j.scr.2021.102558
发表时间：
2021-10
期刊：
Stem cell research
影响因子：
1.2
作者：
Reed X;Cobb MM;Skinbinski G;Roosen D;Kaganovich A;Ding J;Finkbeiner S;Cookson MR
通讯作者：
Cookson MR

Single-cell transcriptomics of human iPSC differentiation dynamics reveal a core molecular network of Parkinson's disease.

DOI：
10.1038/s42003-021-02973-7
发表时间：
2022-01-13
期刊：
Communications biology
影响因子：
5.9
作者：
Novak G;Kyriakis D;Grzyb K;Bernini M;Rodius S;Dittmar G;Finkbeiner S;Skupin A
通讯作者：
Skupin A