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Amyloid elimination by Hsp104 and substrate-optimized variants

Hsp104 和底物优化变体消除淀粉样蛋白

基本信息

批准号：
7429951
负责人：
James Shorter
金额：
$ 236.25万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7429951
关键词：
ATP phosphohydrolase ATPase Domain Academia Adopted Affect Alanine Alzheimer&apos s Disease Amino Acid Sequence Amino Acids Amyloid Amyloid fibers Amyloidosis Animal Model Animals Antibiotics Antibodies Arabidopsis Architecture Award Awareness B-Lymphocytes Bacteria Basement membrane Betaine Binding Biochemical Biochemistry Biological Assay Biological Process Biology Biomedical Research Bos taurus Brain C-terminal Caenorhabditis elegans Cardiac Caring Cattle Cell Death Cell Line Cell Nucleus Cell division Cell physiology Cells Cerebral Amyloid Angiopathy Characteristics Chemicals Class Classification Clinic Clinical Trials Codon Nucleotides Coiled-Coil Domain Collaborations Collection Complex Condition Congo Red Conscious Consensus Craniocerebral Trauma Creativeness Critiques Crowding Cultured Cells Cytoplasm Cytoplasmic Protein Cytosol DNA Shuffling Data Deposition Development Diagnostic Disease Dissection Doctor of Philosophy Dose Dyes Economics Elderly Electric Capacitance Electron Microscopy Electrons Elements Endopeptidases Engineering Ensure Environment Epigallocatechin Gallate Escherichia coli Eukaryotic Cell Event Evolution Exons Fiber Fibers, A Figs - dietary Filament Flowcharts Fluorescence Foundations Frustration Funding Gel Chromatography Generic Drugs Genes Genetic Polymorphism Genetic Variation Genets Goals Golgi Apparatus Green Fluorescent Proteins Head Hela Cells High temperature of physical object Homologous Gene Human Huntington Disease Image Immunoblotting In Vitro Incubated Individual Industry Institutes International Interphase Investigation Journals Kinetics Knowledge Laboratories Lactate Dehydrogenase Length Lewy Bodies Libraries Life Life Expectancy Link Literature Liver London Longevity MJD1 protein Machado-Joseph Disease Mammalian Cell Mammals Maps Mass Spectrum Analysis Measures Melanosomes Membrane Fusion Membrane Proteins Metal exposure Metaphase Methods Microtubules Mining Mission Mitotic Modeling Molds Molecular Molecular Chaperones Molecular Conformation Muramidase Mus Mutagenesis Mutate Mutation N-terminal Natural Selections Natural regeneration Nature Nerve Degeneration Neuroblastoma Neurodegenerative Disorders Neurology Neurons Non-Insulin-Dependent Diabetes Mellitus Nucleotides Occupations Open Reading Frames Parkinson Disease Pathogenesis Pathway interactions Patients Peptide Hydrolases Peptide Sequence Determination Personal Communication Pesticides Pharmaceutical Preparations Phase Phenylalanine Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physiological Plague Plants Play Podospora anserina Polymerase Chain Reaction Population Post-Translational Protein Processing Prevalence Prion Diseases Prions Prize Process Prometaphase Protein Overexpression Protein Structure Initiative Proteins Proteome Public Health Publishing Quality Control Range Rattus Reaction Recombinant Proteins Recombinants Regulation Relative (related person)Research Research Personnel Resistance Resolution Resources Rewards Rifampin Risk Risk Factors Role Running S-nitro-N-acetylpenicillamine Saccharomyces cerevisiae Sampling Science Screening procedure Sedimentation process Seminal Series Shapes Side Signal Pathway Solutions Source Specificity Staging Stress Structure Students Subfamily lentivirinae Substantia nigra structure Substrate Interaction Substrate Specificity Suggestion Sum Surface Switzerland Symptoms System Tauopathies Techniques Temperature Testing Therapeutic Thinking Thioflavin T Three-Dimensional Image Three-Dimensional Imaging Time Tissues Toxic effect Translating Tryptophan Tyrosine Tyrosine Kinase Inhibitor Ubiquitination United States National Institutes of Health Universities Variant Virginia Vision Wages War Water Work Yeast Model System Yeasts age group age related aging population amyloid formation amyloid structure amyloidogenesis anticancer research assay development base career casein kinase II cell type college concept conformer cytotoxic demographics desire directed evolution dopaminergic neuron dosage experience fight against fighting fly forging fungus gene therapy genetic element globular protein human AKAP13 protein human Huntingtin protein human disease immunoreactivity in vivo innovation insight interdisciplinary approach interest islet amyloid polypeptide long term memory member mimetics monomer mouse model mutant neuron loss non-prion novel novel strategies peptide A physical property polyglutamine polypeptide prevent prion hypothesis protein aggregate protein aggregation protein folding protein misfolding protein purification purge reconstitution reconstruction relating to nervous system reproductive reproductive success research study size skills small molecule social stem success synuclein tau Proteins telophase three dimensional structure tissue culture tool trend yeast genetics yeast protein

项目摘要

We are in dire need of innovations to combat several increasingly prevalent and inexorably lethal neurodegenerative disorders, including Alzheimer's and Parkinson's disease, which voraciously devour our social and economic resources. These disorders share a common pathogenic mechanism in which specific proteins misfold into a shared surprisingly generic conformation, termed amyloid. Amyloid fibers of diverse proteins adopt a similar `cross-β' structure, in which the strands of the β-sheets run perpendicular to the fiber axis. Further, highly cytotoxic oligomers possessing a distinct generic structure frequently accumulate prior to fibers. Although the specific protein that forms amyloid and precise localization of the deposits varies in each disease, these shared facets of amyloidogenesis bring hope that therapeutic strategies that target amyloid may have broad applications. The exceptional stability of amyloids, however, including: protease- and SDS-resistance, makes them extraordinarily difficult to clear. Indeed, they are widely perceived as intractable. Remarkably, we have found that a protein- remodeling factor from yeast, Hsp104, can rapidly disassemble amyloid fibers and oligomers comprised of the yeast prion proteins, Sup35 and Ure2. The unprecedented alacrity at which Hsp104 remodels these amyloid structures raises awareness that amyloid conformers are not intractable, and that a cellular factor capable of reversing amyloidogenesis has evolved. Curiously, although highly conserved in plants, bacteria and fungi, Hsp104 has been mysteriously lost from metazoan lineages. We hypothesize that application of Hsp104 to disease-associated amyloids may have broad therapeutic potential. Hence, we aim to: (1) annihilate amyloid fibers, oligomers and associated proteotoxicity of diverse human disease-associated proteins using Hsp104; (2) engineer or evolve substrate-optimized Hsp104 variants that attack select amyloidogenic proteins; and (3) generate Hsp104 or substrate-optimized variant therapies for animal models of amyloid-disorders. These studies will provide the foundations for new approaches to attack the devastating amyloid-disorders that plague humankind.

我们迫切需要创新，以打击几个日益普遍和致命的神经退行性疾病，包括阿尔茨海默氏症和帕金森氏症这些疾病贪婪地吞噬着我们的社会和经济资源。这些疾病具有共同的致病机制，其中特定蛋白质错误折叠成共享的令人惊讶的普通构象，称为淀粉样蛋白。不同蛋白质的淀粉样纤维采用类似的“交叉β”结构，其中β折叠的链垂直延伸到纤维轴。此外，具有不同的通用结构的高细胞毒性寡聚体可用于制备具有不同的通用结构的高细胞毒性寡聚体。结构常常先于纤维积累。虽然形成这种蛋白质的淀粉样蛋白和沉积物的精确定位在每种疾病中各不相同，这些共有的淀粉样蛋白形成的各个方面带来了希望，具有广泛的应用。然而，淀粉样蛋白的特殊稳定性包括：蛋白酶和SDS抗性，使得它们非常难以清除。他们确被广泛认为是棘手的。令人惊讶的是，我们发现一种蛋白质- 来自酵母的重塑因子Hsp 104可以快速分解淀粉样纤维，由酵母朊病毒蛋白Sup 35和Ure 2组成的寡聚体。前所未有的 Hsp 104迅速重塑这些淀粉样结构，淀粉样蛋白构象并不难处理，而且一种能够逆转淀粉样变性已经进化。奇怪的是，尽管在植物中高度保守，和真菌，Hsp 104已经神秘地从后生动物谱系中消失了。我们假设将Hsp 104应用于疾病相关淀粉样蛋白可能具有广泛的治疗作用，潜力因此，我们的目标是：（1）消灭淀粉样纤维，寡聚体和相关的使用Hsp 104的多种人类疾病相关蛋白的蛋白毒性;（2）工程化或进化出攻击选择的淀粉样蛋白的底物优化的Hsp 104变体; 和（3）产生Hsp 104或底物优化的变体疗法，用于以下动物模型：淀粉样蛋白紊乱这些研究将为新的方法提供基础，攻击困扰人类的毁灭性淀粉样蛋白紊乱。