Alternative folding of soluble proteins induced by Aβ42 and Tau in aged cells

衰老细胞中 Aβ42 和 Tau 诱导的可溶性蛋白质的替代折叠

• 批准号: 10448982
• 负责人: Chuankai Zhou
• 金额: $ 53.35万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10448982
• 关键词: 3-Dimensional; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Animal Model; Animals; Biological Process; Biology; Biology of Aging; Cell Line; Cell physiology; Cells; Cellular biology; Defect; Dementia; Disease; Environment; Functional disorder; Future; Goals; Human; Investigation; Kinetics; Mammalian Cell; Messenger RNA; Methods; Modeling; Molecular; Molecular Conformation; Neurofibrillary Tangles; Patients; Peptides; Persons; Pilot Projects; Prevalence; Process; Protein Conformation; Proteins; Proteome; Proteomics; Research; Research Personnel; Resources; Route; Saccharomyces cerevisiae; Saccharomycetales; Shapes; Structure; Thermodynamics; Work; Yeast Model System; Yeasts; abeta accumulation; abeta toxicity; age related; base; cell age; hyperphosphorylated tau; in vivo; metabolic profile; neuron loss; novel; novel therapeutic intervention; polypeptide; prion-like; protein aggregation; protein folding; protein function; protein misfolding; proteostasis; screening; tau Proteins; tau aggregation

ABSTRACT One of the major goals of Alzheimer’s disease (AD) research is to understand how aging and the aggregation of Aβ and/or hyperphosphorylated Tau disrupt the proteostasis and cause progressive neuronal death. The current paradigm of AD research focuses on the amyloid aggregation of Aβ/Tau and the proteins sequestrated by these aggregates. A key untouched question of proteostasis is whether the folding and conformation of soluble proteins, which represent >99% of the proteome, are also changed during aging and AD. As protein conformation determines the specific cellular function(s) of a given protein, the changes in protein folding and conformation will disrupt the original protein functions or allow some polypeptides to acquire age-/AD-specific functions. Nascent polypeptides take kinetically and thermodynamically favorable routes during de novo folding. The energy landscape that determines the folding paths and final native conformations of a protein is shaped by the physiochemical environment surrounding the nascent peptide. Using Saccharomyces cerevisiae (budding yeast) as a model organism and a novel proteomics-structure pipeline, our preliminary studies revealed that changing the cellular folding environment induces the alternative folding of many proteins. As changes in the proteome composition and metabolic profile, two key components of the cellular folding environment, are conserved hallmarks of aging and AD, the goal of this proposal is to understand how aging and AD affect the folding and conformation of the soluble proteins. We propose to use budding yeast for this pilot project as it is a common model organism used to study cellular and molecular mechanisms of aging. Yeast shares numerous biological processes with animals and develops age-related cellular dysfunctions similar to human aging. In addition, the yeast model of AD has been developed to reveal conserved mechanisms of amyloid aggregation and the cellular toxicity of Aβ and Tau. Aging is the major risk factor of AD and other age-related dementias. However, previous studies looked at the young yeast cells expressing human Aβ/Tau proteins. In this proposed project, we want to combine the strength of aging and AD research in yeast to find alternative protein folding induced by Aβ42/Tau in aged cells. We intend to accomplish our goal by 1) determining the prevalence of protein alternative folding induced by aging, and 2) dissecting the effect of Aβ42/Tau on protein folding in aged cells. The hits from our project will be a resource for researchers in the field to determine the gain or loss of protein functions associated with these alternative folding of proteins. This work is expected to reveal the first 3D view of the proteome affected by aging and Aβ42/Tau.

摘要 阿尔茨海默病（AD）研究的主要目标之一是了解衰老和阿尔茨海默病（AD）的聚集是如何发生的。 Aβ和/或过度磷酸化的Tau破坏蛋白质稳态并引起进行性神经元死亡。当前 AD研究的范例集中在Aβ/Tau的淀粉样蛋白聚集和由这些聚集的蛋白螯合。 集料.蛋白质稳态的一个关键的未解决的问题是可溶性蛋白质的折叠和构象， 占蛋白质组的99%以上，在衰老和AD期间也发生了变化。As蛋白构象 决定了特定蛋白质的特定细胞功能，蛋白质折叠和构象的变化 将破坏原始蛋白质功能或允许一些多肽获得年龄/AD特异性功能。 新生多肽在从头折叠过程中采取动力学和化学上有利的途径。的 决定蛋白质折叠路径和最终天然构象的能量景观是由蛋白质的 生理化学环境围绕新生肽。使用酿酒酵母（芽殖酵母） 作为一种模式生物和一种新的蛋白质组学结构管道，我们的初步研究表明， 细胞折叠环境诱导许多蛋白质的交替折叠。蛋白质组的变化 组成和代谢谱，细胞折叠环境的两个关键组成部分，是保守的 衰老和AD的标志，这项提案的目标是了解衰老和AD如何影响折叠， 可溶性蛋白质的构象。我们建议在这个试验项目中使用芽殖酵母，因为它是一种常见的 用于研究衰老的细胞和分子机制的模式生物。酵母分享许多生物 与动物的过程和发展与年龄相关的细胞功能障碍类似于人类衰老。此外该 AD的酵母模型已被开发，以揭示淀粉样蛋白聚集和细胞凋亡的保守机制。 Aβ和Tau的毒性。衰老是AD和其他年龄相关性痴呆的主要危险因素。但此前的 研究着眼于表达人类Aβ/Tau蛋白的年轻酵母细胞。在这个项目中，我们希望 联合收割机结合酵母衰老和AD研究的优势，寻找Aβ42/Tau诱导的替代蛋白折叠 老化的细胞。我们打算通过以下方式实现我们的目标：1）确定蛋白质选择性折叠的普遍性 2）分析Aβ42/Tau对衰老细胞蛋白质折叠的影响。我们的点击率 该项目将成为该领域研究人员确定相关蛋白质功能获得或丧失的资源 蛋白质的交替折叠。这项工作有望揭示受影响蛋白质组的第一个3D视图 衰老和Aβ42/Tau。