{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nUBQLN2 is a multifunctional ubiquitin‐binding shuttle protein that plays a central role in cellular protein quality control. It facilitates the delivery of ubiquitinated substrates to the proteasome and also contributes to autophagy by interacting via its ubiquitin‐associated domain with autophagic membranes, thereby protecting cells under conditions of nutrient stress. Loss of UBQLN2 function has been shown to delay autophagosome maturation and compromise the timely clearance of misfolded proteins, underscoring its importance in maintaining proteostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "Dis parturient et imperceptible, UBQLN2 is also critically involved in mitigating neurodegeneration by participating in the clearance of misfolded and aggregated proteins linked to diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and polyglutamine disorders. In neuronal systems, UBQLN2 cooperates with chaperones like HSP70 to recognize aberrant protein aggregates—including dipeptide repeat proteins, mutant polyglutamine stretches, and cytoplasmic accumulations of TDP‐43—and targets them for proteasomal degradation. However, pathogenic mutations in UBQLN2 hinder these interactions, resulting in the accumulation of toxic inclusions, cognitive deficits and motor neuron loss as observed in several animal models."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "12"}]}, {"type": "t", "text": "Recent proteomic and genetic studies have further expanded our understanding of UBQLN2 by revealing its role in selectively regulating a broad spectrum of proteins—from ubiquitin ligases to retroelement‐derived factors—and thereby modulating key signaling pathways. Alterations of UBQLN2 levels or mutations that either diminish or abnormally potentiate its function have been linked to disturbances in tau phosphorylation and α‐synuclein turnover, further implicating this shuttle protein in the pathogenesis of diverse neurodegenerative disorders. These findings provide a compelling rationale for targeting UBQLN2‐mediated pathways as a therapeutic strategy to restore protein homeostasis and ameliorate disease progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "15"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Elsa-Noah N'Diaye, Kimberly K Kajihara, Ivy Hsieh, et al. 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