Exploring The Brain Enriched E3 Ubiquitin Ligase TRIM9 in Alzheimer's Disease

探索大脑富含 E3 泛素连接酶 TRIM9 在阿尔茨海默病中的作用

• 批准号: 10467201
• 负责人: Stephanie Gupton
• 金额: $ 42.76万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10467201
• 关键词: Actins; Adult; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Anti-Inflammatory Agents; Area; Autopsy; Axon; Biological Assay; Biotin; Brain; Cells; Characteristics; Cognitive; Collaborations; DCC gene; Data; Dementia with Lewy Bodies; Dendritic Spines; Development; Disease Progression; Exhibits; Functional disorder; Future; Genes; Golgi Apparatus; Growth Cones; Health; Hippocampus (Brain); Human; Immunohistochemistry; Impaired cognition; Investigation; Ischemic Stroke; Label; Learning; Ligation; Link; Mass Spectrum Analysis; Membrane; Memory; Morphogenesis; Morphology; Mus; Nerve Degeneration; Nervous system structure; Neurons; Ontology; Paraneoplastic Cerebellar Degeneration; Parkinson' s Dementia; Pathology; Patients; Physiology; Play; Polymerase; Predisposition; Proteins; Proteome; Regulation; Research; Role; Shapes; Stains; Synapses; Testing; Time; Ubiquitination; Wild Type Mouse; Work; aged; base; brain tissue; density; experimental study; follow-up; interest; mouse model; multicatalytic endopeptidase complex; netrin receptor; neuroinflammation; novel; novel marker; overexpression; postsynaptic; protein aggregation; protein biomarkers; synaptic function; target SNARE proteins; tau Proteins; tau aggregation; tau-1; ubiquitin-protein ligase; vasodilator-stimulated phosphoprotein

PROJECT SUMMARY Over the past ten years, my lab has focused on the function of the brain enriched E3 ubiquitin ligase TRIM9. Our interest in TRIM9 originated from our identification of direct interactions between TRIM9 and the actin polymerase VASP, the exocytic synaptic t-SNARE SNAP25 and the netrin receptor DCC. This led us to hypothesize that TRIM9 coordinated cytoskeletal and membrane remodeling during netrin triggered cellular shape change. Our work has shown that TRIM9 regulates cytoskeletal dynamics and membrane remodeling during several critical stages of morphogenesis of developing neurons and that deletion of Trim9 results in a complete loss of spatial learning and memory. Several lines of evidence suggest that TRIM9 may continue to play a critical role in the health and function of the aging neuron. First, TRIM9 enrichment in nervous system continues into adult and is repressed in the brains of human patients with Parkinson’s disease and dementia with Lewy bodies. Our work has shown that deletion of murine Trim9 results in dramatic cognitive impairment, specifically in spatial learning and memory. Trim9-deficient mice exhibit increased neuroinflammation, whereas increasing TRIM9 expression plays neuroprotective roles following ischemic stroke. Finally, TRIM9 is a novel marker for paraneoplastic cerebellar degeneration. Our recent proximity labeling experiments identified a candidate TRIM9 interactome, which contained several proteins implicated in synaptic function and Alzheimer’s disease. Preliminary data indicated TRIM9 affects dendritic spine density. Here, we propose to expand our investigations into how TRIM9 specifically affects the shape and function of the aging neuron, and susceptibility to AD.

项目总结 在过去的十年里，我的实验室一直专注于大脑富含E3泛素的功能 连接酶TRIM9。我们对TRIM9的兴趣源于我们对直接交互作用的识别 在TRIM9和肌动蛋白聚合酶Vasp之间，胞外突触t-SNAP25和 Netrin受体DCC。这导致我们假设TRIM9协调了细胞骨架和 Netrin过程中的膜重塑引发了细胞形态的改变。我们的工作表明， TRIM9在几个关键阶段调节细胞骨架动力学和膜重塑 发育中神经元的形态发生和Trim9的缺失导致完全丧失 空间学习和记忆。有几条证据表明，TRIM9可能会继续发挥作用 对衰老神经元的健康和功能起着至关重要的作用。首先，TRIM9在紧张中浓缩 帕金森氏症患者的大脑系统一直延续到成人，并被抑制 路易体疾病和痴呆症。我们的工作表明，删除小鼠Trim9的结果 在戏剧性认知障碍，特别是在空间学习和记忆方面。Trim9基因缺陷小鼠 表现为神经炎症增加，而TRIM9表达增加 缺血性中风后的神经保护作用。最后，TRIM9是一个新的标记 副肿瘤性小脑变性。我们最近的邻近标记实验发现 候选的TRIM9相互作用体，它包含几个与突触功能有关的蛋白质 和阿尔茨海默氏症。初步数据表明，TRIM9影响树突棘密度。这里, 我们建议扩大对TRIM9如何具体影响形状和 衰老神经元的功能，以及对阿尔茨海默病的敏感性。