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

摘要 Ubiquilin 2（UBQLN 2）的突变最近被确定为额颞叶痴呆的原因， 肌萎缩侧索硬化症（FTD/ALS）与TDP 43沉积相关，UBQLN 2本身已经出现 在相当一部分散发性和家族性FTD/ALS中作为病理学的敏感标志物。UBQLN 2也是 四种密切相关的泛蛋白之一，泛蛋白接头蛋白家族，与泛素依赖性 神经系统中的蛋白质质量控制尽管越来越多的证据表明UBQLN 2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， 大脑健康和疾病的功能仍然知之甚少。此外， UBQLN 2突变导致FTD/ALS的原因尚不清楚。目前的建议调查了这些关键差距， 知识我们的主要目标是确定UBQLN 2介导的FTD/ALS的致病机制， 深入了解驱动FTD/ALS中TDP 43沉积和神经变性的细胞途径。在三 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）定义驱动聚合的分子特性， 突变体UBQLN 2，2）在小鼠模型中探索UBQLN 2聚集的功能后果，和3） 研究突变体UBQLN 2如何改变神经元中的TDP 43稳态。拟议的研究基于：新颖 对野生型和突变型UBQLN 2的不同特性的生物化学见解;新产生的小鼠 表达野生型或突变体UBQLN 2的模型，其在突变体中选择性地显示稳健的聚集病理学， UBQLN 2小鼠;一个完整的蛋白质组学筛选表明，野生型UBQLN 2与两个 其他脑表达的泛素，UBQLN 1和UBQLN 4;以及TDP 43阳性细胞质表达的证据。 斑点在突变UBQLN 2小鼠的神经元中积累，提供了一条探索 UBQLN 2和TDP 43。所提出的多系统方法大大增加了发现的概率 FTD/ALS的疾病机制，并实现我们的长期目标，找到治疗方法， 一系列致命的、与年龄相关的神经退行性疾病。

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.