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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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos 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&apos 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

项目摘要

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.

项目概要在过去的十年里，我的实验室一直专注于大脑富集E3泛素的功能连接酶 TRIM9。我们对 TRIM9 的兴趣源于我们对直接相互作用的识别 TRIM9 和肌动蛋白聚合酶 VASP、胞吐突触 t-SNARE SNAP25 和 netrin 受体 DCC。这使我们推测 TRIM9 协调细胞骨架和 netrin 期间的膜重塑引发细胞形状变化。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 Trim9 的缺失会导致神经元发育完全丧失空间学习和记忆。多项证据表明 TRIM9 可能会继续发挥作用对衰老神经元的健康和功能至关重要。首先，TRIM9在神经中的富集该系统持续到成年，并在帕金森病患者的大脑中受到抑制路易体疾病和痴呆。我们的工作表明，删除小鼠 Trim9 会导致严重的认知障碍，特别是空间学习和记忆。 Trim9 缺陷小鼠表现出神经炎症增加，而增加 TRIM9 表达则发挥作用缺血性中风后的神经保护作用。最后，TRIM9 是一个新颖的标记副肿瘤性小脑变性。我们最近的邻近标记实验确定了候选 TRIM9 相互作用组，其中包含几种与突触功能有关的蛋白质和阿尔茨海默病。初步数据表明 TRIM9 影响树突棘密度。这里，我们建议扩大我们的研究范围，以了解 TRIM9 如何具体影响形状和老化神经元的功能和 AD 的易感性。