Dissecting the aging-associated decline in cellular proteostasis - Project 1

剖析与衰老相关的细胞蛋白质稳态下降 - 项目 1

• 批准号: 10432032
• 负责人: JUDITH FRYDMAN
• 金额: $ 42.19万
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10432032
• 关键词: Address; Affect; Age; Aging; Alzheimer' s Disease; Amyloid beta-Protein; Autophagocytosis; Biogenesis; Biological Assay; Biological Models; Caenorhabditis elegans; Cell Survival; Cells; Complex; Defect; Degenerative Disorder; Disease; Disease model; Equilibrium; Functional disorder; Genomics; Human; Huntington Disease; Huntington gene; Impairment; Intervention; Late-Onset Disorder; Life Cycle Stages; Link; Longevity; Modeling; Molecular; Molecular Chaperones; Monitor; Mus; Neurodegenerative Disorders; Output; Parkinson Disease; Pathway interactions; Phase; Predisposition; Process; Protein Biosynthesis; Proteins; Proteome; Proteomics; Quality Control; Reporter; Resistance; Saccharomyces cerevisiae; Solubility; Stress; System; Testing; Translating; Translations; Ubiquitin; Ubiquitination; Work; Yeast Model System; Yeasts; age related; aged; environmental chemical; experimental study; improved; induced pluripotent stem cell; insight; link protein; misfolded protein; mouse model; multicatalytic endopeptidase complex; polyglutamine; polypeptide; preservation; prevent; programs; protein aggregation; protein folding; protein function; protein misfolding; proteostasis; resilience; ribosome profiling; synergism; tau Proteins

Project 1 – Frydman - Dissecting the aging-associated decline in cellular proteostasis Project Summary: The ability to maintain a functional proteome by preserving protein homeostasis, or proteostasis, is essential for cell viability. Yet, this ability declines during the process of aging. Such a collapse in proteostasis results in the accumulation of misfolded and aggregated proteins that are a hallmark of late-onset diseases including, most notably, a wide range of neurodegenerative diseases including Alzheimer’s, Parkinson’s and Huntington’s Diseases. However, it remains largely unknown what cellular changes are responsible for the loss of protein homeostasis and the accumulation of damaged proteins during aging. We propose to define the mechanisms and consequences of this proteostasis decline in order to better understand what cellular interventions could improve the aging process and ameliorate age-related diseases. Proteostasis is maintained through the interplay of molecular chaperones, which are essential for protein folding and function, and quality control factors, including the ubiquitin-proteasome system and autophagy, which target misfolded proteins for elimination. Accumulating evidence suggests that the proteostasis balance is disrupted during aging. Yet, our understanding of how aging alters the interplay of proteostasis regulators is far from complete. This Project will examine several phases that regulate the life cycle of a protein, including translational fidelity, chaperone function, and misfolded protein management, to determine what cellular changes dictate the widespread proteostasis collapse associated with aging. Importantly, we will examine how the presence of aggregation-prone disease-linked proteins such as A-beta, tau and polyQ-expanded Huntingtin exon1 affect the interplay between proteostasis disfunction and aging. This will provide substantial insight into how age-dependent modulation of these processes might contribute to the decline in proteostasis, and associated decline in cell viability, that is a primary hallmark of aging and several late-onset human neurodegenerative diseases. In order to elucidate at a molecular level how aging affects the folding of newly translated proteins and the management of misfolded and stress-denatured proteins, we plan to exploit our collective expertise across a variety of models of aging to: (i) Examine how aging affects biogenesis and folding of newly made proteins and (ii) Determine how aging affects the management of misfolded and aggregation-prone proteins

项目1 - Frydman -剖析衰老相关的细胞蛋白质稳态下降 项目概要： 通过保持蛋白质稳态来维持功能蛋白质组的能力是必不可少的 用于细胞活力。然而，这种能力在衰老过程中会下降。这种蛋白质稳定的崩溃导致 错误折叠和聚集的蛋白质的积累是晚发型疾病的标志， 最值得注意的是，包括阿尔茨海默氏症、帕金森氏症和亨廷顿氏症在内的各种神经退行性疾病 疾病然而，它仍然在很大程度上是未知的细胞变化是负责蛋白质的损失 体内平衡和老化过程中受损蛋白质的积累。我们建议定义这些机制 以及这种蛋白质稳态下降的后果，以便更好地了解细胞干预可以 改善衰老过程和改善与年龄有关的疾病。 蛋白质稳态是通过分子伴侣的相互作用来维持的，分子伴侣是蛋白质合成所必需的。 折叠和功能，以及质量控制因素，包括泛素-蛋白酶体系统和自噬， 其靶向错误折叠的蛋白质以消除。越来越多的证据表明，蛋白质稳态平衡 在衰老过程中被破坏。然而，我们对衰老如何改变蛋白质稳态调节因子相互作用的理解是， 远远没有完成。本项目将研究调节蛋白质生命周期的几个阶段，包括 翻译保真度，伴侣蛋白功能和错误折叠蛋白质管理，以确定什么细胞 这些变化决定了与衰老相关的广泛的蛋白质稳态崩溃。重要的是，我们将研究如何 易聚集疾病相关蛋白如A-β、tau和polyQ-扩增亨廷顿蛋白的存在 exon 1影响蛋白质稳态功能障碍和衰老之间的相互作用。这将提供实质性的洞察力， 这些过程的年龄依赖性调节如何导致蛋白质稳态的下降，以及 相关的细胞活力下降，这是衰老的主要标志， 神经退行性疾病 为了在分子水平上阐明衰老如何影响新翻译的蛋白质的折叠， 管理错误折叠和应力变性蛋白质，我们计划利用我们的集体专业知识， 老化的各种模型：（一）检查老化如何影响生物发生和折叠的新制作的 蛋白质和（ii）确定衰老如何影响错误折叠和易聚集蛋白的管理 蛋白