GDPD2 (glycerophosphodiester phosphodiesterase domain containing 2), also known as GDE3, is a six-transmembrane ecto-phospholipase that functions as a GPI-anchor-cleaving enzyme with critical roles in lipid signaling and cell differentiation 1. The protein exhibits glycerophosphoinositol-specific phosphodiesterase activity, catalyzing the hydrolysis of lysophosphatidylinositol (LPI) to generate monoacylglycerols and inositol phosphates 23. A key physiological function involves acting as a signaling switch: GDE3 converts the GPR55 agonist LPI into 2-arachidonoylglycerol (2-AG), a cannabinoid receptor ligand, thereby redirecting signaling between these pathways 23. In bone metabolism, GDE3 promotes osteoblast differentiation while suppressing proliferation through this lipid-signaling mechanism 3. In gliogenesis, GDE3 negatively regulates oligodendrocyte precursor cell (OPC) proliferation by releasing soluble CNTFRα via GPI-anchor cleavage, enhancing ciliary neurotrophic factor signaling 4. Disease relevance includes X-linked neurodevelopmental disorders, where Xq13.1 microduplications encompassing GDPD2 present with delayed speech development, intellectual disability, and neuropsychiatric symptoms 5. Additionally, GDPD2 expression increases in response to soluble tau species (A152T variant) in neurodegeneration models, potentially contributing to astrocytic dysfunction 6.