AP2A2 encodes the alpha-2 subunit of adaptor protein complex 2 (AP-2), a heterotetrameric protein essential for clathrin-dependent endocytosis 1. AP2A2 functions as a core component of the AP-2 complex, which acts as a clathrin adaptor that binds directly to both the clathrin lattice and membrane lipids/proteins to facilitate formation of clathrin-coated vesicles destined for early endosomes 2. The AP-2 alpha subunit recognizes specific endocytosis signal motifs in transmembrane cargo proteins and serves as a scaffolding platform through its C-terminal appendage domain for recruiting endocytic accessory proteins 3. AP2A2 dysfunction contributes to multiple diseases. Mutations in AP2A2 cause hereditary spastic paraplegia, characterized by defective endocytosis of transferrin receptors, increased axon initial segment length, and neuronal dysfunction 4. In Alzheimer's disease, AP2A2 specifically colocalizes with neurofibrillary tangles containing tau pathology, and genetic polymorphisms near AP2A2 correlate with tau proteinopathy severity 32. Additionally, higher AP2A2 expression in bronchial epithelial cells associates with asthma severity and exacerbations 5, while AP2A2 variants show suggestive association with chr11 bronchitis in COPD 6. These findings establish AP2A2 as a critical regulator of endocytic trafficking whose dysfunction has significant implications for neurological and pulmonary diseases.