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

项目概要 神经退行性疾病，例如肌萎缩侧索硬化症 (ALS) 和额颞叶病 痴呆症（FTD）正在加剧公共卫生挑战，有效的治疗方法仍然存在 缺乏。 ALS/FTD 研究中至少出现了两个主要主题： 病因与 RNA 代谢和蛋白质稳态有关。然而，其机制 RNA 和蛋白质稳态并不完全独立。 UBQLN2 是一种蛋白质质量 与 ALS/FTD 相关的控制因素。 UBQLN2 的突变与 ALS/FTD 和 UBQLN2 免疫反应性存在于 ALS/FTD 和其他神经退行性疾病中 条件。我们已经确定了 UBQLN2 在对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- FUS 的处理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）。在这里我们将表征 iPSC 含有 ADRD 相关突变的品系，以开发更好的 ADRD 疾病模型。的 该项目旨在对 iPSC 系进行深度质量控制和分子表型分析，以产生 可预测且可靠的模型。研究结果不仅能提供临床参考 这种形式的神经退行性疾病（例如 ALS/FTD）的相关模型，而且 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.