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

• 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
• 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

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，例如肌萎缩性侧索硬化症（ALS）和额颞 痴呆症（FTD）正在增加公共卫生挑战，有效治疗仍在 缺乏。从ALS/FTD的研究中出现了至少两个主要主题 病因与RNA代谢和蛋白稳态有关。但是，RNA和 基于蛋白质的发病机理可能是相互依存的。在这里，我们建议解开钥匙 在RNA和 蛋白质稳态。 FUS是与ALS/FTD相关的RNA结合蛋白之一。 最近，我们在FUS中发现了RNA结合蛋白的新作用。 直接调节microRNA的活性，这些活动是小的RNA，起作用至关重要 基因表达的调节剂。此外，考虑到FUS蛋白能够 进行相分离，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，我们建议阐明先前未知的 胁迫颗粒和蛋白质聚集体的异常形成的机制 破坏ALS/FTD相关蛋白保持的RNA稳态。此外，我们的 研究将致力于发现内置的细胞质量控制系统 保持RNA/蛋白质稳态，并了解这些系统如何出现 疾病。我们为这一领域做出贡献的独特潜力既是概念和技术：我们 已经开发了生化/c的独特组合。秀丽隐杆线/哺乳动物系统学习 神经退行性的机制以及我们最近的成功实现了未来计划。这 调查结果不仅将为关键的疾病分子原因提供新的理解 ALS基因，但也提出了利用蜂窝防御系统的新策略 预防和治疗ALS和其他相关神经退行性疾病的相关形式。我们 预测通过我们的研究工作取得的进步最终将导致新 治疗干预措施以解决这些毁灭性疾病。