iProXProteomicsYitao QiMus Musculushttp://www.iprox.org/page/project.html?id=IPX0017909000qiyitao@snnu.edu.cnShaanxi Normal UniversityiProXfalseMechanistic study of SENP2-PCYT1A axis regulating synaptic pruning that results in anxiety-like behaviorAnxiety disorder, one of the most common mental illnesses, is emerging as a significant public health challenge. Glial regulation of neuronal synaptic pruning offers a novel therapeutic avenue for anxiety; however, it remains unclear whether SUMO modification is involved in this regulatory process. In this study, we demonstrate that both global and microglia-specific SENP2 knockout mice exhibit anxiety-like behaviors coupled with aberrant synaptic pruning, whereas neuronal-specific knockout animals do not show these phenotypes. Moreover, SENP2 specifically modulates LC3-associated phagocytosis (LAP) in microglia and removes SUMO modifications from the target protein PCYT1A. We propose that the SENP2–PCYT1A signaling axis in microglia/astrocyte governs LAP pathway activity, thereby maintaining synaptic pruning homeostasis and preventing the onset of anxiety-like behaviors. Accordingly, this project will (1) define the precise role of LAP in microglial/astrocyte synaptic pruning, (2) elucidate the molecular mechanism by which SUMOylation regulates key factors in the LAP pathway, and (3) investigate how the SENP2–PCYT1A axis modulates synaptic stability and anxiety-related behaviors. These findings not only advance our understanding of SUMO modification in microglia–neuron immune crosstalk but also provide novel insights into potential targeted interventions and precision therapies for anxiety-related mental disorders.Tue Jun 23 00:00:00 BST 2026PXD08010410090