Mechanisms of RNA and Protein Dysregulations in ALS/FTD Associated with FUS and Ubiquilin 2

与 FUS 和泛素 2 相关的 ALS/FTD 中 RNA 和蛋白质失调的机制

基本信息

批准号：
10318610
负责人：
Jiou Wang
金额：
$ 52.73万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10318610
关键词：
Address Aging Amyotrophic Lateral Sclerosis Behavior Biochemical Biological Models Caenorhabditis elegans Complex Disease Disease Pathway Etiology Future Gene Expression Gene Expression Regulation Genes Genetic Transcription Goals Heat shock proteins Homeostasis Impairment Intervention Lead Light Link Mediating Messenger RNA MicroRNAs Modeling Molecular Molecular Chaperones Mutation Nerve Degeneration Neurodegenerative Disorders Pathogenesis Pathogenicity Pathway interactions Phase Phase Transition Process Proteins Public Health Quality Control RNA RNA Processing RNA metabolism RNA-Binding Proteins Regulation Regulator Genes Regulatory Pathway Research Ribonucleoproteins Role Small RNA Societies System Therapeutic Intervention Toxic effect Work base effective therapy frontotemporal lobar dementia-amyotrophic lateral sclerosis fused in sarcoma insight misfolded protein mutant new therapeutic target novel novel therapeutic intervention prevent protein aggregation proteostasis stress granule success ubiquilin

项目摘要

Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are increasing public health challenges, for which effective treatment is still lacking. At least two major themes have emerged from the studies of ALS/FTD, concerning etiology related to both RNA metabolism and protein homeostasis. However, the RNA- and protein-based pathogenesis are likely to be interdependent. Here we propose to unravel the key molecular pathways in the common pathogenic processes at the intersection of RNA and protein homeostasis. FUS is one of the RNA-binding proteins that have linked to ALS/FTD. Recently, we discovered a new role for RNA-binding proteins, as exemplified by FUS, in the direct regulation of the activities of microRNAs, which are small RNAs functioning as critical regulators of gene expression. Moreover, considering the notion that FUS protein is capable of undergoing phase separation, assembling into stress granules, and forming protein aggregates, and building on our preliminary evidence, we propose to elucidate the previously unrecognized mechanisms through which aberrant formation of stress granules and protein aggregates disrupt the RNA homeostasis maintained by ALS/FTD associated proteins. Furthermore, our studies will be directed at uncovering the cellular quality control systems that are built in to maintain the RNA/protein homeostasis and understanding how these systems go awry in diseases. Our unique potential to contribute to this field is both conceptual and technical: We have developed a unique combination of biochemical/C. elegans/mammalian systems to study the mechanisms of neurodegeneration, and our recent success bodes well for future plans. The findings will not only provide novel understandings of the molecular causes of disease for key ALS genes but also suggest new strategies for harnessing the cellular defense system to prevent and treat the relevant forms of ALS and other related neurodegenerative diseases. We predict that the advances gained through our research efforts will eventually lead to new therapeutic interventions to address these devastating diseases.

神经退行性疾病，例如肌萎缩侧索硬化症 (ALS) 和额颞叶病痴呆症（FTD）正在加剧公共卫生挑战，有效的治疗方法仍然存在缺乏。 ALS/FTD 的研究中至少出现了两个主要主题：病因与 RNA 代谢和蛋白质稳态有关。然而，RNA-和基于蛋白质的发病机制可能是相互依赖的。在这里我们建议解开关键 RNA 和 RNA 交叉点的常见致病过程中的分子途径蛋白质稳态。 FUS 是与 ALS/FTD 相关的 RNA 结合蛋白之一。最近，我们发现了 RNA 结合蛋白的新作用，如 FUS 所示，在直接调节 microRNA 的活性，这些小 RNA 发挥着关键作用基因表达的调节因子。此外，考虑到 FUS 蛋白能够经历相分离，组装成应力颗粒，并形成蛋白质聚集体，并以我们的初步证据为基础，我们建议阐明以前未被认识到的应激颗粒和蛋白质聚集体异常形成的机制破坏 ALS/FTD 相关蛋白维持的 RNA 稳态。此外，我们的研究将旨在揭示内置的细胞质量控制系统维持 RNA/蛋白质稳态并了解这些系统如何出错疾病。我们为这一领域做出贡献的独特潜力既体现在概念上，也体现在技术上：我们开发了生化/C的独特组合。秀丽隐杆线虫/哺乳动物系统的研究神经退行性疾病的机制，以及我们最近的成功预示着未来的计划。这研究结果不仅将为关键疾病的分子原因提供新的理解 ALS 基因还提出了利用细胞防御系统的新策略预防和治疗相关形式的 ALS 和其他相关的神经退行性疾病。我们预测通过我们的研究努力所取得的进步最终将带来新的成果治疗干预措施来解决这些毁灭性的疾病。