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.