PTPRD (protein tyrosine phosphatase receptor type D) is a receptor-type protein tyrosine phosphatase functioning as a neuronal cell adhesion molecule and synaptic specifier 1. The protein bidirectionally induces pre- and post-synaptic neuronal differentiation through trans-synaptic interactions with IL1RAP and IL1RAPL1, and mediates pre-synaptic differentiation via SLITRK2 interaction. PTPRD exhibits phosphatase activity and mediates trans-synaptic signaling critical for synapse assembly and dendritic spine morphogenesis. PTPRD demonstrates pleiotropic involvement in neurological phenotypes. Mouse models and human genetics implicate PTPRD in addiction, restless leg syndrome, cognitive impairment/intellectual disability, mood lability, and obsessive-compulsive disorder 1. Recent studies reveal asprosin-PTPRD signaling in cerebellar Purkinje neurons modulates thirst behavior, suggesting potential therapeutic targets for thirst disorders 2. Beyond neurobiology, PTPRD functions as a tumor suppressor gene. It is frequently inactivated through homozygous deletions and epigenetic downregulation in hepatocellular carcinomas, with expression loss in 82.6% of primary HCC samples 3. PTPRD variants associate with marginal zone lymphomas [PMID:37294969; 48], nonalcoholic fatty liver disease susceptibility 5, blood pressure response to β-blockers, and resistant hypertension 6. These findings establish PTPRD as a pleiotropic molecule relevant to neurological, metabolic, and cardiovascular disorders.