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: 10401555
• 负责人: Jiou Wang
• 金额: $ 41.79万
• 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/10401555
• 关键词: Aging; Alzheimer' s disease related dementia; Behavior; Cell Line; Disease; Disease model; Etiology; Lead; Link; Modeling; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Outcome Study; Pathogenicity; Pathologic; Phase Transition; Proteins; Public Health; Quality Control; RNA; RNA Processing; RNA metabolism; Role; Societies; System; Therapeutic; Therapeutic Intervention; Work; clinically relevant; effective therapy; frontotemporal lobar dementia-amyotrophic lateral sclerosis; human stem cells; immunoreactivity; induced pluripotent stem cell; insight; molecular phenotype; mutant; proteostasis; stem cell model; stress granule; ubiquilin

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.

项目摘要 神经退行性疾病，例如肌萎缩性侧索硬化症（ALS）和额颞 痴呆症（FTD）正在增加公共卫生挑战，有效治疗仍在 缺乏。至少有两个从ALS/FTD的研究中出现的主要主题 病因与RNA代谢和蛋白稳态有关。但是，机制 RNA和蛋白质稳态并非完全独立。 UBQLN2是一种蛋白质质量 与ALS/FTD相关的控制因子。 UBQLN2中的突变已与 ALS/FTD和UBQLN2免疫反应性在ALS/FTD和其他神经退行性中发现 状况。我们已经确定了ubqln2在拮抗异常相变的作用 和压力颗粒的形成突变型FU，可能破坏RNA-的行为 FUS的处理功能并导致神经变性。诱导的多能干细胞 （IPSC）衍生模型已成为研究的工具实验系统 神经退行性疾病的病理机制和治疗干预措施 包括阿尔茨海默氏病和相关痴呆症（ADRD）。在这里，我们将表征IPSC 具有与ADRD相关的突变的线路，以开发更好的ADRD疾病模型。这 项目针对IPSC线的深层控制和分子表型来生成 可预测可靠的模型。研究的结果不仅将在临床上提供 这种形式的神经变性疾病（例如ALS/FTD）的相关模型，也 对致病机制以及治疗应用产生见解 破坏性疾病。