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和蛋白质的稳态并不是完全独立的。UBQLN 2是一种蛋白质质量 与ALS/FTD相关的控制因素。UBQLN2的突变与 在ALS/FTD和其他神经退行性疾病中发现UBQLN 2免疫反应性 条件我们已经确定了UBQLN 2在拮抗异常相变中的作用， 和突变FUS的应激颗粒形成，这些行为可能破坏RNA- 处理FUS的功能并导致神经变性。诱导多能干细胞 （iPSC）衍生的模型已成为研究 神经退行性疾病的病理机制和治疗干预 包括阿尔茨海默病和相关痴呆症（ADRD）。在这里，我们将描述iPSC 携带ADRD相关突变的细胞系，以开发更好的ADRD疾病模型。的 该项目旨在对iPSC细胞系进行深入的质量控制和分子表型分析， 可预测和可靠的模型。这些研究的结果将不仅提供临床 这种形式的神经变性疾病如ALS/FTD的相关模型， 深入了解致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.