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

整合质量控制：UBQLN2 在年龄相关神经退行性疾病中的研究

• 批准号: 10200456
• 负责人: Magdalena I Ivanova
• 金额: $ 15.6万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10200456
• 关键词: Adaptor Signaling Protein; Address; Affect; Animal Model; Automobile Driving; Behavior; Biochemical; Biochemistry; Biophysics; Brain; Brain Diseases; Cells; Cytoplasmic Inclusion; Deposition; Disease; Goals; Homeostasis; Impairment; In Vitro; Knowledge; Link; Mediating; Microscopy; Molecular; Mus; Mutation; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neurons; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Physiological; Play; Probability; Property; Proteins; Proteomics; Quality Control; Role; Route; Seeds; Solubility; Structure; System; Technical Expertise; Techniques; Toxic effect; Transgenic Mice; UBQLN1 gene; Ubiquitin; Ubiquitin family; age related neurodegeneration; base; brain health; dimer; disease-causing mutation; frontotemporal lobar dementia-amyotrophic lateral sclerosis; insight; mouse model; mutant; neurotoxicity; novel; protein TDP-43; protein aggregation; proteostasis; receptor; ubiquilin

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.

抽象的 最近发现泛素 2 (UBQLN2) 突变是导致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) 以及 UBQLN2 本身已经出现 作为大部分散发性和家族性 FTD/ALS 病理学的敏感标志物。 UBQLN2 也是 四种密切相关的泛素之一，是涉及泛素依赖性的泛素接头蛋白家族 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 大脑健康和疾病中的功能仍然知之甚少。此外，其机制 UBQLN2 突变导致 FTD/ALS 的情况尚不清楚。当前的提案调查了这些关键差距 知识。我们的主要目标是定义 UBQLN2 介导的 FTD/ALS 的致病机制并 深入了解 FTD/ALS 中驱动 TDP43 沉积和神经变性的细胞途径。三分之内 采用互补方法（生物化学、动物模型和自动化）的具体目标 显微镜），我们的研究团队将寻求 1）定义驱动聚集的分子特性 突变体 UBQLN2，2) 探索小鼠模型中 UBQLN2 聚集的功能后果，以及 3) 研究突变体 UBQLN2 如何改变神经元中 TDP43 稳态。拟议的研究建立在：新颖 对野生型和突变型 UBQLN2 独特特性的生化见解；新生成的鼠标 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合病理学 UBQLN2小鼠；完整的蛋白质组学筛选证明野生型 UBQLN2 与两者相互作用 其他脑表达的泛素、UBQLN1 和 UBQLN4；以及 TDP43 阳性细胞质的证据 puncta 在突变型 UBQLN2 小鼠的神经元中积累，为探索之间的功能联系提供了一条途径 UBQLN2 和 TDP43。所提出的多系统方法大大增加了发现的可能性 FTD/ALS 的疾病机制，并实现我们寻找治疗途径的长期目标 一系列致命的、与年龄相关的神经退行性疾病。

项目成果

Aggregation and the Intrinsic Structural Disorder of Dipeptide Repeat Peptides of C9orf72-Related Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Characterized by NMR.

NMR 表征的 C9orf72 相关肌萎缩侧索硬化症和额颞叶痴呆的二肽重复肽的聚集和内在结构紊乱。

• DOI: 10.1021/acs.jpcb.1c08149
• 发表时间: 2021
• 期刊: The journal of physical chemistry. B
• 作者: Krishnarjuna,Bankala;Ivanova,MagdalenaI;Ramamoorthy,Ayyalusamy
• 通讯作者: Ramamoorthy,Ayyalusamy

Conformational Tuning of Amylin by Charged Styrene-Maleic-Acid Copolymers.

• DOI: 10.1016/j.jmb.2021.167385
• 发表时间: 2022-01-30
• 期刊: Journal of molecular biology
• 影响因子: 5.6
• 作者: Sahoo BR;Souders CL 2nd;Watanabe-Nakayama T;Deng Z;Linton H;Suladze S;Ivanova MI;Reif B;Ando T;Martyniuk CJ;Ramamoorthy A
• 通讯作者: Ramamoorthy A

Biophysical processes underlying cross-seeding in amyloid aggregation and implications in amyloid pathology.

• DOI: 10.1016/j.bpc.2020.106507
• 发表时间: 2021-02
• 期刊: Biophysical chemistry
• 影响因子: 3.8
• 作者: Ivanova MI;Lin Y;Lee YH;Zheng J;Ramamoorthy A
• 通讯作者: Ramamoorthy A