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: 10530653
• 负责人: Jiou Wang
• 金额: $ 51.62万
• 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/10530653
• 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; 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; 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，如肌萎缩侧索硬化症(ALS)和额颞部 痴呆症(FTD)是越来越多的公共卫生挑战，对此仍有有效的治疗方法 缺乏。ALS/FTD的研究至少出现了两个主要主题，涉及 病因学与RNA代谢和蛋白质动态平衡有关。然而，RNA-和 基于蛋白质的发病机制可能是相互依存的。在这里，我们建议解开关键 常见致病过程中RNA和RNA交叉点的分子途径 蛋白质动态平衡。FUS是与ALS/FTD相关的RNA结合蛋白之一。 最近，我们发现了RNA结合蛋白的一个新角色，如FUS，在 对microRNAs活性的直接调节，microRNAs是起关键作用的小RNA 基因表达的调节者。此外，考虑到FUS蛋白能够 经过相分离，组装成应力颗粒，形成蛋白质聚集体， 基于我们的初步证据，我们建议澄清之前未被认识到的 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动态平衡。此外，我们的 研究的目标将是揭示内置到 维持RNA/蛋白质的动态平衡，并了解这些系统是如何出错的 疾病。我们为这一领域做出贡献的独特潜力既有概念上的，也有技术上的：我们 开发了一种独特的生化/线虫/哺乳动物系统组合来研究 神经退化的机制，以及我们最近的成功，对未来的计划来说是个好兆头。这个 这些发现不仅将为关键的疾病的分子病因提供新的理解 ALS基因，也提出了利用细胞防御系统来 预防和治疗相关形式的肌萎缩侧索硬化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获得的进步最终将导致新的 针对这些毁灭性疾病的治疗干预措施。