{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRabphilin‐3A (RPH3A) is a critical component of the neuronal secretory machinery that regulates synaptic vesicle docking, fusion, and neurotransmitter release. In healthy neurons, RPH3A interacts with small GTPases—most notably Rab3A—to ensure efficient vesicle exocytosis; however, in neurodegenerative diseases such as Lewy body disease and Huntington’s disease, alterations in RPH3A expression and its association with the SNARE complex have been linked to impaired synaptic function. In Alzheimer’s disease, reduced RPH3A levels correlate with dementia severity and cholinergic deafferentation, while in Parkinsonian models the interaction of RPH3A with the GluN2A subunit of NMDA receptors is enhanced, contributing to aberrant receptor localization and dyskinetic behavior. Moreover, rare variants in RPH3A have been implicated in neurodevelopmental disorders through destabilization of GluN2A at the plasma membrane."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nStructural and mechanistic investigations have revealed that RPH3A contains specialized C2 domains that mediate its Ca²⁺-dependent and phosphoinositide-specific binding—a property that is essential for drawing vesicle and plasma membranes into close apposition during exocytosis. In secretory cell models such as human sperm, RPH3A acts as an effector of Rab27 by recruiting a guanine nucleotide exchange factor (GRAB), which in turn facilitates Rab3A activation and ensures the tight regulation of the acrosome reaction."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its prominent roles in neurons, RPH3A is also expressed in non‐neuronal cells where it supports specialized secretory and structural functions. In podocytes, for example, the co‐localization of RPH3A with Rab3A and synaptic proteins suggests that it contributes to the organization of the cytoskeletal network required for maintaining the integrity of the glomerular filtration barrier—a finding that is reinforced by its upregulation in proteinuric kidney diseases. Similarly, in neutrophils, the polarized recruitment of RPH3A to domains rich in phosphatidylinositol-4-phosphate and its cooperation with ARF6 are essential for directing key signaling molecules necessary for firm adhesion to inflamed endothelia."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "E Dalfó, M Barrachina, J L Rosa, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Missense variants in RPH3A cause defects in excitatory synaptic function and are associated with a clinically variable neurodevelopmental disorder."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genet Med (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.gim.2023.100922"}], "href": "https://doi.org/10.1016/j.gim.2023.100922"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37403762"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37403762"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Jaime Guillén, Cristina Ferrer-Orta, Mònica Buxaderas, et al. 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