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

项目摘要 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研究中出现的至少两个主要主题，涉及 病因学与RNA代谢和蛋白质动态平衡有关。然而，它的作用机制 RNA和蛋白质动态平衡并不是完全独立的。UBQLN2是一种蛋白质性质 已与ALS/FTD相关的控制因素。UBQLN2中的突变与 ALS/FTD和UBQLN2免疫反应在ALS/FTD和其他神经退行性变中被发现 条件。我们已经确定了UBQLN2在拮抗反常相变中的作用 以及突变FU的应激颗粒形成，这些行为可能会扰乱RNA- FUS的加工功能，并导致神经退行性变。诱导的多能干细胞 (IPSC)衍生的模型已成为研究生物多样性的重要实验系统 神经退行性疾病的病理机制及治疗干预 包括阿尔茨海默病和相关痴呆症(ADRD)。在这里，我们将描述IPSC 含有ADRD相关突变的株系，以开发更好的ADRD疾病模型。这个 该项目旨在对IPSC品系进行深度质量控制和分子表型鉴定，以产生 可预测和可靠的模型。研究的结果不仅将在临床上提供 这种形式的神经退行性疾病的相关模型，如ALS/FTD，但也 洞察疾病的发病机制以及治疗应用 毁灭性的疾病。

Project Summary 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 that have emerged from the studies of ALS/FTD, concerning etiology related to both RNA metabolism and protein homeostasis. However, the mechanisms of RNA and protein homeostasis are not completely independent. UBQLN2 is a protein quality control factor that has been linked to ALS/FTD. Mutations in UBQLN2 have been linked to ALS/FTD, and UBQLN2 immunoreactivity is found in ALS/FTD and other neurodegenerative conditions. We have identified a role for UBQLN2 in antagonizing the aberrant phase transition and stress granule formation of mutant FUS, behaviors that potentially disrupt the RNA- processing functions of FUS and lead to neurodegeneration. The induced pluripotent stem cells (iPSC)-derived models have become instrumental experimental systems for study the pathological mechanisms and therapeutic interventions for neurodegenerative diseases including Alzheimer’s disease and related dementias (ADRD). Here we will characterize iPSC lines that harbor ADRD-related mutations in order to develop better ADRD disease models. The project is aimed at deep quality control and molecular phenotyping of the iPSC lines to generate predictable and reliable models. The outcome of the studies will not only provide clinically relevant models for this form of neurodegeneration diseases such as ALS/FTD but also generate insights into the pathogenic mechanisms as well as therapeutic applications for the devasting diseases.