Investigation of TRIM9 in cell shape change in the aging brain

项目摘要 在过去的九年里，我的实验室一直专注于大脑富含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 发育中的神经元的形态发生。这不仅包括发展上的变化， 相关的阶段，如生长锥形态，轴突和树突分支，但后来 与突触功能相关的形态发生阶段，如树突棘密度。几 一系列证据表明，TRIM 9可能继续在健康和功能方面发挥关键作用。 衰老的神经元。首先，TRIM 9在神经系统中的富集持续到成人， 帕金森病和路易痴呆症患者的大脑中受到抑制 尸体我们的工作表明，小鼠Trim 9的缺失导致显著的认知功能障碍。 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表达发挥神经保护作用， 缺血性中风最后，TRIM 9是副肿瘤性小脑变性的新标志物。 在这里，我们建议扩大我们的调查如何TRIM 9具体影响的形状和 衰老神经元的功能，以及对AD的易感性。

PROJECT SUMMARY Over the past nine 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. This includes not only changes in developmentally relevant stages such as growth cone morphology, and axonal and dendritic branching, but later morphogenetic stages with synaptic function relevance, such as dendritic spine density. 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. Here, we propose to expand our investigation into how TRIM9 specifically affects the shape and function of the aging neuron, and susceptibility to AD.