Are all Protein Aggregates Toxic?

所有蛋白质聚集体都有毒吗？

• 批准号: 10580153
• 负责人: Ashutosh Tiwari
• 金额: $ 43.93万
• 依托单位: MICHIGAN TECHNOLOGICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-22 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580153
• 关键词: Acids; Address; Alzheimer' s Disease; Amyloid beta-42; Atomic Force Microscopy; BODIPY; Biochemical; Biological Assay; Biophysics; Cell Line; Cell Survival; Cell physiology; Cellular Membrane; Characteristics; Collaborations; Collection; Communities; Data; Deposition; Dyes; Embryo; Fluorescent Dyes; Fluorescent Probes; Functional disorder; Goals; Human; Hydrophobic Surfaces; Hydrophobicity; In Vitro; Insulin; Lead; Literature; Measures; Membrane Proteins; Metabolic; Muramidase; Nature; Neurodegenerative Disorders; Neurons; Organelles; Oxidation-Reduction; Pathologic; Pathway interactions; Peptides; Physiological; Play; Predisposition; Property; Proteins; Role; Scanning Electron Microscopy; Shapes; Solubility; Structure; Sulfonic Acids; Techniques; Temperature; Testing; Therapeutic Intervention; Tissues; Toxic effect; aqueous; base; biophysical properties; cytotoxicity; endoplasmic reticulum stress; flexibility; gel electrophoresis; kidney cell; misfolded protein; mitochondrial dysfunction; monomer; neuroblastoma cell; novel; protein aggregation; protein degradation; quantum; therapeutically effective

PROJECT SUMMARY Abnormal aggregation and deposition of misfolded proteins have been recognized as a common pathological hallmark of several neurodegenerative diseases. The goal of this project is to identify unique physicochemical properties of aggregates, shared by a large number of structurally diverse proteins (e.g. Aβ42 peptide, insulin and lysozyme), that are toxic. In general, the scientific community agrees that soluble aggregates of proteins, especially those that are in the form of proto-fibrils, are noxious. These aggregates can cause toxicity by several mechanisms such as, aberrant interaction with cellular membranes, organelles, interaction with other proteins that may be critical for cellular functions, or by clogging the protein degradation and clearing pathways. However, there is paucity in literature showing a clear correlation between aggregated proteins shape (e.g. amorphous, globular, or fibril), flexibility (e.g. flexible, or rigid), size (e.g. monomer, oligomer, or fibril), and hydrophobicity, with its associated toxicity. Our findings on Aβ42 peptide aggregation and toxicity shows that increased surface hydrophobicity of protein aggregates can contribute to an increase in cellular toxicity. We hypothesize that flexible protein aggregates with increased surface hydrophobicity may hold the key to cellular toxicity. To test this hypothesis, we will use simple but unrelated proteins (e.g. insulin and lysozyme) which are normally not toxic and compare the properties of the aggregates of these proteins with Aβ42 peptide aggregates whose role in Alzheimer’s disease is well known. We will generate diverse aggregated structures from these proteins, characterize their biochemical and biophysical properties including size, shape, flexibility, relative hydrophobicity, and measure their associated toxicity. This will also help us address: “Is it the sequence or the unique physicochemical properties of the aggregated protein that is critical for its toxicity”. As a result, it will help us identify key physicochemical properties shared by protein aggregates that are central to their toxicity.

项目概要 错误折叠蛋白的异常聚集和沉积已被认为是一种常见的病理现象。 多种神经退行性疾病的标志。该项目的目标是确定独特的物理化学 聚集体的特性，由大量结构多样的蛋白质（例如 Aβ42 肽、胰岛素 和溶菌酶），这些都是有毒的。一般来说，科学界同意可溶性蛋白质聚集体， 尤其是那些原纤维形式的，是有毒的。这些聚集体可通过以下方式引起毒性： 多种机制，例如与细胞膜、细胞器的异常相互作用、与其他物质的相互作用 可能对细胞功能至关重要的蛋白质，或阻碍蛋白质降解和清除的蛋白质 途径。然而，很少有文献表明聚集蛋白之间存在明确的相关性 形状（例如无定形、球状或原纤维）、柔性（例如柔性或刚性）、尺寸（例如单体、低聚物或 原纤维）和疏水性及其相关的毒性。我们对 Aβ42 肽聚集和毒性的发现 研究表明，蛋白质聚集体表面疏水性的增加有助于增加细胞 毒性。我们假设具有增加的表面疏水性的柔性蛋白质聚集体可能保持 细胞毒性的关键。为了检验这个假设，我们将使用简单但不相关的蛋白质（例如胰岛素和 溶菌酶），通常无毒，并将这些蛋白质的聚集体的特性与 Aβ42 肽聚集体在阿尔茨海默病中的作用众所周知。我们将产生多样化的 这些蛋白质的聚集结构，表征其生化和生物物理特性，包括 尺寸、形状、柔韧性、相对疏水性，并测量它们相关的毒性。这也将帮助我们 地址：“关键是聚集蛋白的序列还是独特的理化性质？ 因为它的毒性”。因此，它将帮助我们确定蛋白质聚集体共有的关键物理化学特性 这是其毒性的核心。