PLPPR5 (phospholipid phosphatase related 5) is a brain-enriched integral membrane protein that functions as a phospholipid phosphatase involved in neuronal plasticity and development. Functionally, PLPPR5 induces filopodia formation and promotes neurite growth in a CDC42-independent manner while impeding neurite growth inhibitory-mediated axonal retraction 1. The protein is highly expressed in high-plasticity brain regions, particularly the hippocampus, with lower expression in cortex, cerebellum, and striatum, and is specifically expressed in neuron-rich spinal cord regions during development, suggesting critical roles in neuronal regulation 1. PLPPR5 participates in dendritic spine occurrence and stability 1. Regarding disease relevance, PLPPR5 knockout aggravates hypoxic-ischemic brain injury in neonatal models and partially impairs the neuroprotective effects of melatonin treatment, with knockout mice showing deficits in learning, memory, and motor function compared to wild-type littermates 1. Additionally, PLPPR5 dysregulation has been identified as a key hub protein in the signal transduction pathway disrupted in chr1 stress-induced depression, contributing to altered synaptic plasticity and neuronal function in major depressive disorder 2. These findings suggest PLPPR5 is essential for normal neuronal development and protective against neurodevelopmental and neuropsychiatric disorders.