{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nN‐glycanase 1 (NGLY1) is a highly conserved cytosolic enzyme that catalyzes the cleavage of intact N‐linked glycans from misfolded glycoproteins targeted for proteasomal degradation—a key step in the endoplasmic reticulum‐associated degradation (ERAD) pathway. Early studies in yeast demonstrated that this peptide:N‐glycanase not only facilitates the quality control of newly synthesized glycoproteins but also localizes to both the nucleus and cytosol, emphasizing its central role in cellular homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its catalytic role in deglycosylation, NGLY1 is emerging as a multifunctional protein that couples protein quality control with diverse cellular processes. Structural studies have revealed functional domains—such as the PUB domain—that mediate interactions with key cofactors (e.g., p97 and HR23), thereby facilitating the recognition and removal of misfolded glycoproteins. In addition, NGLY1 influences pathways beyond ERAD, including the modulation of mitochondrial homeostasis, autophagic flux, and even transcriptional regulation of aquaporins, which may occur through non‐enzymatic mechanisms. Cellular and biochemical investigations in patient‐derived fibroblasts and model systems have demonstrated that loss of NGLY1 activity results in the accumulation of aberrant proteins, dysregulation of cellular stress responses, and altered metabolism of free oligosaccharides—all of which contribute to cellular dysfunction. These insights, supported by studies employing compound screening and proteomic analyses, have also opened avenues for targeting associated ubiquitin ligase complexes as potential therapeutic strategies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nClinically, mutations in NGLY1 result in an autosomal recessive congenital disorder of deglycosylation (NGLY1‐CDDG) that manifests with multisystem involvement—including global developmental delay, neuromotor impairment, seizures, liver dysfunction, and ocular abnormalities. Detailed analyses in patient‐derived cells and cerebral organoid models have linked NGLY1 deficiency to impaired neural precursor differentiation, disrupted stress signaling, and altered proteostatic mechanisms that contribute to the neurodevelopmental and multisystem phenotypes. Recent studies have further expanded the phenotypic spectrum and incidence of this disorder, underscoring the importance of NGLY1 in human development and proteostasis regulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}, {"type": "fg_f", "ref": "8"}, {"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "T Suzuki, H Park, N M Hollingsworth, et al. 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