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

神经退行性疾病，如肌萎缩性侧索硬化症（ALS）和额颞叶神经退行性疾病， 痴呆症（FTD）是日益增加的公共卫生挑战，有效的治疗仍然是 缺乏ALS/FTD研究中至少出现了两个主要主题， 病因学与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 在RNA和RNA的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，我们发现了一个新的作用，RNA结合蛋白，如FUS，在 直接调节microRNA的活性，microRNA是小RNA， 基因表达的调节器。此外，考虑到FUS蛋白能够 发生相分离，组装成应激颗粒，并形成蛋白质聚集体， 在我们初步证据的基础上，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。而且我们的 研究将针对揭示细胞质量控制系统， 维持RNA/蛋白质的稳态，并了解这些系统是如何出错的， 疾病我们在这一领域的独特潜力包括概念和技术两个方面： 已经开发出一种独特的生化/C. elegans/哺乳动物系统研究 神经退化的机制，我们最近的成功预示着未来的计划。的 这些发现不仅将为疾病的分子病因提供新的理解， ALS基因，但也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 我预测，通过我们的研究努力所取得的进展最终将导致新的 治疗干预措施来应对这些毁灭性疾病。

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.