Integrating Quality Control: Studies of UBQLN2 in Age-Related Neurodegeneration

摘要 泛素2(UBQLN2)基因突变最近被确认为额颞叶痴呆的原因之一 与TDP43沉积相关的肌萎缩侧索硬化症(FTD/ALS)和UBQLN2本身已经出现 在相当一部分散发性和家族性FTD/ALS中，作为一个敏感的病理标志物。UBQLN2也是 四个密切相关的泛素之一，泛素适配器蛋白家族，与泛素依赖有关 神经系统中的蛋白质质量控制。尽管越来越多的证据表明UBQLN2和其他 泛素在许多由蛋白质积累定义的与年龄相关的神经退行性疾病中，其 对大脑健康和疾病的功能仍然知之甚少。此外，通过哪些机制 UBQLN2的突变导致FTD/ALS尚不清楚。目前的提案调查了以下方面的关键差距 知识。我们的主要目标是确定UBQLN2介导的FTD/ALS的致病机制，并 深入了解在FTD/ALS中驱动TDP43沉积和神经变性的细胞通路。在三年内 采用互补方法(生物化学、动物模型和自动化)的特定目标 显微镜)，我们的研究团队将寻求1)定义驱动聚集的分子属性 突变体UBQLN2，2)探索UBQLN2聚集在小鼠模型中的功能后果，以及3) 研究突变体UBQLN2如何改变神经元中的TDP43稳态。拟议的研究以：小说为基础 对野生型和突变型UBQLN2不同特性的生化洞察；新生的小鼠 表达野生型或突变型UBQLN2的模型在突变型中选择性地显示出强大的聚集病理 UBQLN2小鼠；完整的蛋白质组学筛查显示，野生型UBQLN2与两者相互作用 其他脑表达的泛素，UBQLN1和UBQLN4；以及证据表明，TDP43阳性的细胞质 斑点蛋白在突变的UBQLN2小鼠的神经元中积累，为探索两者之间的功能联系提供了一条途径 UBQLN2和TDP43。提出的多系统方法极大地增加了发现的概率 FTD/ALS的疾病机制和我们寻找治疗途径的长期目标的实现 一系列与年龄相关的致命性神经退行性疾病。

Abstract Mutations in Ubiquilin2 (UBQLN2) were recently identified as a cause of Frontotemporal Dementia and Amyotrophic Lateral Sclerosis (FTD/ALS) associated with TDP43 deposition, and UBQLN2 itself has emerged as a sensitive marker of pathology in a substantial portion of sporadic and familial FTD/ALS. UBQLN2 is also one of four closely related ubiquilins, a family of ubiquitin adaptor proteins implicated in ubiquitin-dependent protein quality control in the nervous system. Although mounting evidence implicates UBQLN2 and other ubiquilins in numerous age-related neurodegenerative diseases defined by protein accumulation, their functions in brain health and disease remain poorly understood. Moreover, the mechanisms by which mutations in UBQLN2 cause FTD/ALS are unknown. The current proposal investigates these critical gaps in knowledge. Our primary goals are to define pathogenic mechanisms in UBQLN2-mediated FTD/ALS and to gain insight into the cellular pathways driving TDP43 deposition and neurodegeneration in FTD/ALS. In three specific aims employing complementary approaches (biochemistry, animal models, and automated microscopy), our investigative team will seek to 1) define the molecular properties driving aggregation of mutant UBQLN2, 2) explore the functional consequences of UBQLN2 aggregation in mouse models, and 3) investigate how mutant UBQLN2 alters TDP43 homeostasis in neurons. The proposed studies build on: novel biochemical insights into the distinct properties of wild type and mutant UBQLN2; newly generated mouse models expressing wild type or mutant UBQLN2 that show robust aggregate pathology selectively in mutant UBQLN2 mice; a completed proteomics screen demonstrating that wild-type UBQLN2 interacts with the two other brain-expressed ubiquilins, UBQLN1 and UBQLN4; and evidence that TDP43-positive cytoplasmic puncta accumulate in neurons of mutant UBQLN2 mice, offering a pathway to explore functional links between UBQLN2 and TDP43. The proposed multi-system approach greatly increases the probability of uncovering disease mechanisms in FTD/ALS and achieving our long-term objective of finding routes to therapy for this spectrum of fatal, age-related neurodegenerative diseases.