{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nAmphiphysin 1 is a multifunctional adaptor protein that plays a central role in clathrin‐mediated endocytosis and the regulation of actin dynamics. It directly interacts with N‑WASP to trigger Arp2/3‐dependent actin polymerization, a mechanism essential for the formation of membrane ruffles and phagocytic cups in neuronal and Sertoli cells. Furthermore, under conditions of neural hyperexcitation, calpain‐mediated cleavage of amphiphysin 1 disrupts its interactions with dynamin and other partners, thereby transiently inhibiting synaptic vesicle endocytosis. A novel phosphorylation event at threonine 260 also links amphiphysin 1 to seizure‐induced signaling cascades."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRegulatory phosphorylation by CDKL5 further modulates amphiphysin 1 activity—diminishing its affinity for endophilin—and implicates this protein in synaptic vesicle recycling and neuronal development, with dysregulation linked to neurodevelopmental disorders. In addition, amphiphysin 1 contributes to the proper formation of tubulobulbar complexes in Sertoli cells, a process crucial for timely spermatid release. Neuronal systems also exploit coordinated interactions between amphiphysin 1 and distinct dynamin isoforms to tailor endocytic processes to the specific demands of small clear synaptic vesicle recycling versus larger dense-core vesicle replenishment."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its canonical endocytic functions, amphiphysin 1 exerts important roles in immune and neurodegenerative contexts. In macrophages, for example, the aberrant retention of amphiphysin isoforms on pathogen‐containing vacuoles facilitates the evasion of host defense mechanisms. In Alzheimer’s disease, cleavage of amphiphysin 1 by asparagine endopeptidase generates an N‑terminal fragment that not only impairs clathrin-mediated endocytosis but also promotes p35-to-p25 conversion, leading to CDK5 activation and enhanced tau hyperphosphorylation—thereby contributing to synaptic dysfunction and cognitive deficits."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hiroshi Yamada, Sergi Padilla-Parra, Sun-Joo Park, et al. 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