PRSS12 (neurotrypsin/motopsin) is a mosaic serine protease with critical roles in neuronal development and cognition. 1 The protein is secreted from neurons and localizes to dendrites, soma, and axons, where it exhibits enzymatic activity against synthetic substrates and cleaves the proteoglycan agrin. 1 PRSS12 modulates neuronal plasticity through proteolytic action and cell-cell interactions; it interacts with seizure-related gene 6 to regulate neuronal morphology and neurite outgrowth. 2 In the developing brain, PRSS12 shows spatiotemporal expression patterns unique to the prefrontal cortex and has been implicated in primate-specific neural circuit formation. 3 Loss of PRSS12 function causes autosomal recessive intellectual developmental disorder in humans. 1, 4 Studies in motopsin knockout mice revealed preferential effects on social behaviors and decreased hippocampal dendritic spine density, with reduced CREB phosphorylation following spatial learning and social interaction. 4 Beyond neurodevelopment, PRSS12 associates with muscle mass and strength phenotypes through neuromuscular junction function, with specific genetic variants showing significant associations with grip strength and lean mass. 5 PRSS12 expression is downregulated in esophageal squamous cell carcinoma, where high expression correlates with improved survival, suggesting tumor-suppressive functions. 6