Kim_2026_Nat.Neurosci__

Glioma pathophysiology is robustly regulated by interactions with neurons. Key to these interactions is the role of neuroligin-3 (NLGN3), a synaptic adhesion molecule shed in response to neuronal activity that functions as a paracrine factor crucial for glioma growth. Here we elucidate the mechanistic pathway whereby shed NLGN3 interacts with glioma and their normal glial counterparts. NLGN3 binds to chondroitin sulfate proteoglycan 4 (CSPG4, also known as NG2) on both glioma and healthy oligodendrocyte precursor cells (OPCs), facilitating CSPG4 shedding by ADAM10. NLGN3-CSPG4 interactions alter membrane tension, thereby activating mechanotransducers, primarily PIEZO1, leading to membrane depolarization and subsequent ADAM10-mediated CSPG4 shedding. The NLGN3-CSPG4-PIEZO1 pathway maintains OPCs in an undifferentiated, stem-like state and promotes glioma proliferation, underscoring its dual roles in healthy and malignant contexts.