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Aging and chronic oxidative stress are critical contributors to neurodegeneration. UBQLN2, a ubiquitin-related protein, aids in protein degradation and protects against oxidative stress. In ALS neurons harboring UBQLN2 mutations, oxidative stress accelerates pathological changes, yet the precise mechanisms remain unclear. Using induced motor neurons (iMNs) derived from UBQLN2 P497H iPSCs, we observed ALS-like phenotypes, including TDP-43 mislocalization, increased cell death, and reduced viability. Sodium arsenite (SA)-induced oxidative stress triggered stress granule formation, while autophagy dysfunction exacerbated neuronal degeneration. CHX and bosutinib treatments reduced ubiquitinated protein accumulation and alleviated degeneration, highlighting potential therapeutic pathways. These findings emphasize the role of chronic oxidative stress and stress granule formation in UBQLN2 ALS, offering insights into novel therapeutic targets.<\/jats:p>","DOI":"10.3390\/ijms252413448","type":"journal-article","created":{"date-parts":[[2024,12,16]],"date-time":"2024-12-16T04:14:52Z","timestamp":1734322492000},"page":"13448","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Chronic Oxidative Stress and Stress Granule Formation in UBQLN2 ALS Neurons: Insights into Neuronal Degeneration and Potential Therapeutic Targets"],"prefix":"10.3390","volume":"25","author":[{"given":"Ao","family":"Gu","sequence":"first","affiliation":[{"name":"MOE Key Lab of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics of the School of Life Sciences, Central South University, Changsha 410017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4245-2879","authenticated-orcid":false,"given":"Yiti","family":"Zhang","sequence":"additional","affiliation":[{"name":"MOE Key Lab of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics of the School of Life Sciences, Central South University, Changsha 410017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianfeng","family":"He","sequence":"additional","affiliation":[{"name":"MOE Key Lab of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics of the School of Life Sciences, Central South University, Changsha 410017, China"},{"name":"Department of Cell Biology, School of Life Sciences, Central South University, Changsha 410017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8260-7935","authenticated-orcid":false,"given":"Mingri","family":"Zhao","sequence":"additional","affiliation":[{"name":"MOE Key Lab of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics of the School of Life Sciences, Central South University, Changsha 410017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingjie","family":"Ding","sequence":"additional","affiliation":[{"name":"MOE Key Lab of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics of the School of Life Sciences, Central South University, Changsha 410017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanxi","family":"Liu","sequence":"additional","affiliation":[{"name":"MOE Key Lab of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics of the School of Life Sciences, Central South University, Changsha 410017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianing","family":"Xiao","sequence":"additional","affiliation":[{"name":"MOE Key Lab of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics of the School of Life Sciences, Central South University, Changsha 410017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiali","family":"Huang","sequence":"additional","affiliation":[{"name":"MOE Key Lab of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics of the School of Life Sciences, Central South University, Changsha 410017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1558-1448","authenticated-orcid":false,"given":"Mujun","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, School of Life Sciences, Central South University, Changsha 410017, China"},{"name":"Hunan Key Laboratory of Basic and Applied Hematology, Central South University, Changsha 410017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2633-7096","authenticated-orcid":false,"given":"Xionghao","family":"Liu","sequence":"additional","affiliation":[{"name":"MOE Key Lab of Rare Pediatric Diseases & Hunan Key Laboratory of Medical Genetics of the School of Life Sciences, Central South University, Changsha 410017, China"},{"name":"Hunan Key Laboratory of Basic and Applied Hematology, Central South University, Changsha 410017, China"},{"name":"Hunan Key Laboratory of Animal Model for Human Diseases, Central South University, Changsha 410017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e398","DOI":"10.1212\/NXG.0000000000000398","article-title":"ALS in Danish Registries: Heritability and links to psychiatric and cardiovascular disorders","volume":"6","author":"Trabjerg","year":"2020","journal-title":"Neurol. 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