A model system for pathological transitions of RNA-binding protein aggregates

RNA结合蛋白聚集体病理转变的模型系统

• 批准号: 10263214
• 负责人: Brian Matthew Zid
• 金额: $ 19.3万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10263214
• 关键词: Address; Affect; Age; Aging; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Behavior; Biological Markers; Biological Models; Biophysics; Cell Death; Cell physiology; Cells; Chemicals; Communities; Cytoplasmic Granules; Data; Disease; Genes; Goals; Human; Individual; Link; Liquid substance; Longevity; Mammals; Mass Spectrum Analysis; Measures; Methods; Microfluidic Microchips; Microfluidics; Microscopy; Molecular; Mothers; Mutation; Nature; Nerve Degeneration; Neurodegenerative Disorders; Pathogenicity; Pathologic; Pathway interactions; Phase Transition; Phenotype; Physiological; Process; Proteins; RNA-Binding Proteins; Research; Research Proposals; Resources; Role; Saccharomyces cerevisiae; Saccharomycetales; Solid; Stress; Structure; System; Testing; Time; Work; Yeasts; age related neurodegeneration; aged; base; cell age; daughter cell; fused in sarcoma; insight; link protein; live cell imaging; messenger ribonucleoprotein; novel; novel strategies; predictive marker; protein aggregation; proteostasis; stressor

Project Summary/Abstract Age-related neurodegenerative diseases are a class of incurable diseases that result in the progressive degeneration of neuronal cells. Recent research has pointed to a role for RNA-binding proteins in age- related neurodegenerative diseases: as many RNA-binding proteins have aggregation-prone intrinsically disordered regions, they accumulate in pathological inclusions of various neurodegenerative diseases, and mutations in a number of RNA-binding proteins have been linked to neurodegenerative diseases. For many RNA-binding proteins linked to neurodegenerative diseases they also become concentrated into mRNP granules during stressful conditions. This formation of mRNP granules during stress is beneficial to cells, as disruption of these granules sensitizes cells to a variety of stressors. Our hypothesis is that mRNP granules initially form as non-toxic, potentially beneficial structures during the aging process, but that they undergo a pathological transition that leads to cell death. This proposal seeks to establish a model system for this pathological transition using yeast in combination with microfluidics to follow the formation and transition of mRNP granules during aging. To accomplish this, we will (Aim 1) build on our preliminary data exploring the pathogenicity of large age-induced mRNP granules using microfluidics and fluorescent microscopy to follow single yeast cells across their entire lifespan. Secondly, we will (Aim 2) identify markers for this pathological transition by measuring changes in the material state and macromolecular composition of age-induced mRNP granules. In the long term these markers will help to elucidate the mechanistic details of this transition. Together this system will establish a new paradigm to understand basic details on how mRNP granules can transition from non-toxic, potentially beneficial structures to pathological inclusions that drive the degeneration of cells. As many genes and pathways are conserved from yeast to mammals, including pathways that affect aging, this research may point to new targets to help ameliorate neurodegenerative diseases in humans.

项目摘要/摘要 与年龄相关的神经退行性疾病是一类无法治愈的疾病，导致渐进性 神经元细胞的变性。最近的研究表明，RNA结合蛋白在年龄中的作用 相关的神经退行性疾病：由于许多RNA结合蛋白具有聚集 本质上无序的区域，它们积聚在各种的病理夹杂物中 神经退行性疾病和许多RNA结合蛋白中的突变已与 神经退行性疾病。对于许多与神经退行性疾病相关的RNA结合蛋白 在压力条件下，它们也集中在MRNP颗粒中。这种形成 压力期间的MRNP颗粒对细胞有益，因为这些颗粒的破坏使细胞敏感到A 各种压力源。我们的假设是MRNP颗粒最初形成是无毒的，潜在的 在衰老过程中的有益结构，但他们经历了导致的病理过渡 到细胞死亡。该提案旨在建立一个模型系统，用于使用 酵母与微流体的结合遵循MRNP颗粒的形成和过渡期间 老化。为此，我们将（AIM 1）建立在我们的初步数据上，以探索的致病性 使用微流体和荧光显微镜遵循单酵母的大型年龄诱导的MRNP颗粒 细胞在整个寿命中。其次，我们将（AIM 2）确定该病理的标记 通过测量材料状态的变化和年龄诱导的大分子组成的过渡 MRNP颗粒。从长远来看，这些标记将有助于阐明此的机械细节 过渡。该系统将共同建立一个新的范式，以了解有关如何 MRNP颗粒可以从无毒的，潜在的有益结构转变为病理夹杂物 驱动细胞的变性。由于许多基因和途径从酵母到 哺乳动物，包括影响衰老的途径，这项研究可能指出新的目标以帮助 改善人类的神经退行性疾病。