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.

项目摘要 错误折叠蛋白质的异常聚集和沉积已被认为是一种常见的病理学 几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 聚集体的性质，由大量结构不同的蛋白质（例如Aβ42肽、胰岛素 和溶菌酶），它们是有毒的。总的来说，科学界同意可溶性蛋白质聚集体， 特别是那些原纤维形式的是有害的。这些聚集体可通过以下方式引起毒性： 几种机制，如与细胞膜、细胞器的异常相互作用，与其他细胞的相互作用， 可能对细胞功能至关重要的蛋白质，或通过堵塞蛋白质降解和清除 途径。然而，很少有文献表明聚集的蛋白质之间存在明显的相关性 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）和疏水性以及其相关的毒性。我们对Aβ42肽聚集和毒性的研究结果 表明蛋白质聚集体表面疏水性的增加可以有助于细胞增殖的增加。 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了蛋白质的稳定性。 细胞毒性的关键为了验证这一假设，我们将使用简单但不相关的蛋白质（例如胰岛素和 溶菌酶），并将这些蛋白质的聚集体的性质与 Aβ42肽聚集体在阿尔茨海默病中的作用是众所周知的。我们将创造多样化的 从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，并测量它们相关毒性。这也将帮助我们 地址：“是聚合蛋白的序列还是独特的物理化学性质是关键 其毒性”。因此，它将帮助我们确定蛋白质聚集体共享的关键物理化学性质 是它们毒性的核心