{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nUBQLN2 is a multifunctional ubiquitin‐binding shuttle protein central to cellular proteostasis. It normally binds ubiquitinated substrates via its C‐terminal ubiquitin‐associated (UBA) domain and delivers them to the proteasome through its N‐terminal ubiquitin‐like (UBL) domain, thereby facilitating protein degradation via the ubiquitin–proteasome system as well as coordinating aspects of autophagy. In addition, UBQLN2 acts as a chaperone for cytosolically exposed transmembrane domains and modulates the biogenesis of protein complexes such as the γ‐secretase by regulating presenilin fragment levels. Disruption of these functions by disease‐linked mutations impairs protein clearance, promotes abnormal protein aggregation (including of TDP‐43), and ultimately contributes to motor neuron degeneration in conditions such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in protein clearance, UBQLN2 dynamically engages in liquid–liquid phase separation and regulates the assembly and maturation of stress granules under cellular stress conditions. Through its proline‐rich and intrinsically disordered regions, UBQLN2 can form liquid‐like condensates that sequester aberrant proteins; however, ALS/FTD‐linked mutations often perturb this phase behavior, leading to altered droplet dynamics and a shift toward more solid‐like, pathogenic aggregates. These findings illustrate how UBQLN2’s regulated phase separation is essential for maintaining cellular homeostasis and efficient autophagic flux."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "19", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic studies reveal that mutations in UBQLN2—especially those clustered in its PXX repeat region—are associated with a broad spectrum of neurodegenerative phenotypes, ranging from classical ALS to ALS with dementia and pure forms of frontotemporal dementia. These mutations disrupt UBQLN2’s interactions with key substrates such as TDP‐43 and interfere with its ability to shuttle misfolded proteins for degradation, thereby precipitating the formation of ubiquitin‐positive inclusions and synaptic dysfunction. Such clinical heterogeneity underscores the pivotal role of UBQLN2 in neuronal protein homeostasis and highlights its potential as a therapeutic target."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "24", "end_ref": "26"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kylie J Walters, Maurits F Kleijnen, Amanda M Goh, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature10353"}], "href": "https://doi.org/10.1038/nature10353"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21857683"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21857683"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Johannes Brettschneider, Vivianna M Van Deerlin, John L Robinson, et al. 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