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

项目摘要 在过去的十年里，我的实验室一直致力于研究大脑中富含E3的泛素的功能 连接酶TRIM 9。我们对TRIM 9的兴趣源于我们对直接相互作用的识别 TRIM 9和肌动蛋白聚合酶VASP之间，胞吐突触t-SNARE SNAP 25和 netrin受体DCC。这使我们假设TRIM 9协调细胞骨架和细胞外基质。 netrin期间的膜重塑引发细胞形状改变。我们的工作表明， TRIM 9在几个关键阶段调节细胞骨架动力学和膜重塑 Trim 9的缺失导致神经元的完全丧失， 空间学习和记忆。一些证据表明，TRIM 9可能会继续发挥作用， 在老化神经元的健康和功能中起着关键作用。首先，TRIM 9富集在神经系统中， 这个系统持续到成年，在帕金森氏症患者的大脑中受到抑制 路易体病和痴呆症。我们的工作表明，小鼠Trim 9的缺失导致 严重的认知障碍，特别是在空间学习和记忆方面。Trim 9缺陷小鼠 表现出增加的神经炎症，而增加TRIM 9表达起作用， 缺血性卒中后的神经保护作用。最后，TRIM 9是一种新的标记物， 副肿瘤性小脑变性我们最近的邻近标记实验确定了一个 候选TRIM 9相互作用体，其含有涉及突触功能的几种蛋白质 和老年痴呆症初步数据表明TRIM 9影响树突棘密度。在这里， 我们建议扩大我们的调查，以了解TRIM 9如何特别影响形状， 衰老神经元的功能，以及对AD的易感性。

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.