{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe γ‐secretase complex is a multimeric, intramembrane‐cleaving protease essential for processing type I transmembrane proteins such as the amyloid precursor protein (APP) and Notch. Central to the complex is nicastrin, which governs assembly, maturation, substrate recruitment, and subcellular trafficking. Nicastrin undergoes extensive post‐translational modifications—including N‐glycosylation and S‐palmitoylation—that target it to specialized cholesterol‐rich membrane microdomains and promote its association with presenilin and other γ‐secretase components. Disruption of nicastrin expression or its proper processing not only impairs γ‐secretase activity and alters the generation of amyloid β peptides but also affects downstream signaling pathways (for example, Notch) and other regulatory processes such as neprilysin expression. In addition, factors regulating its stability (for instance, ubiquitin ligases like Synoviolin and kinases such as SGK1) further modulate the turnover of nicastrin and, hence, γ‐secretase function, linking these mechanisms to pathologies including Alzheimer’s disease, certain cancers, and immune‐related disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nA distinct set of studies has revealed that the EF‐hand domain protein EFhd2 (also known as Swiprosin‑1) functions as a versatile, calcium‐dependent adaptor that regulates cytoskeletal dynamics and signal transduction in diverse cell types. In neuronal systems, EFhd2 associates with pathological tau aggregates and modulates synaptic vesicle trafficking, thereby contributing to aspects of neurodegeneration and memory formation. In immune cells—including B cells, mast cells, T cells, and macrophages—EFhd2 facilitates receptor‐mediated calcium fluxes, stabilizes immunological synapses, and orchestrates actin reorganization to influence cell migration, apoptosis, and cytokine production. Altogether, EFhd2 emerges as a key mediator of both neuronal and immune signaling processes, with its activity tightly regulated by post‑translational modifications and interactions that ultimately impact cell viability, plasticity, and responsiveness in health and disease."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "24", "end_ref": "34"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Dun-Sheng Yang, Anurag Tandon, Fusheng Chen, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Nicastrin is required for assembly of presenilin/gamma-secretase complexes to mediate Notch signaling and for processing and trafficking of beta-amyloid precursor protein in mammals."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci (2003)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12716934"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12716934"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Jinhe Li, Gregory J Fici, Chai-An Mao, et al. 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