Sigma-1R–Pom121 axis preserves nuclear transport and integrity in poly-PR-induced C9orf72 ALS
Nucleocytoplasmic transport disruption contributes to the pathogenesis of C9orf72-associated amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Among the dipeptide repeat proteins translated from G4C2-repeat RNA, poly-PR is particularly toxic, compromising nuclear envelope integrity an...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-08-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996125002086 |
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| author | Chun-Yu Lin Hsuan-Cheng Wu Ru-Huei Fu Eddie Feng-Ju Weng Wen-Chi Hsieh Tsung-Ping Su Hsiang-En Wu Shao-Ming Wang |
| author_facet | Chun-Yu Lin Hsuan-Cheng Wu Ru-Huei Fu Eddie Feng-Ju Weng Wen-Chi Hsieh Tsung-Ping Su Hsiang-En Wu Shao-Ming Wang |
| author_sort | Chun-Yu Lin |
| collection | DOAJ |
| description | Nucleocytoplasmic transport disruption contributes to the pathogenesis of C9orf72-associated amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Among the dipeptide repeat proteins translated from G4C2-repeat RNA, poly-PR is particularly toxic, compromising nuclear envelope integrity and transport. Here, we revealed that poly-PR reduced expression of the nucleoporin Pom121 in NSC-34 cells and in an AAV-mediated poly-PR42 mouse model, resulting in cytoplasmic mislocalization of the neuroprotective transcription factor ATF3 and nuclear envelope damage. Pom121 overexpression restored nuclear ATF3 localization and alleviated poly-PR-induced toxicity. We further identified Sigma-1 receptor (Sigma-1R) as a stabilizer of Pom121 that preserved nuclear integrity and ATF3 function under oxidative stress. Overexpression of Sigma-1R, Pom121, or ATF3 rescued poly-PR-induced cytotoxicity. Our findings defined a protective Sigma-1R/Pom121/ATF3 axis and suggested this pathway as a therapeutic target in C9orf72-linked ALS. |
| format | Article |
| id | doaj-art-bd44bd76aaef40c1bf1a167ae3aff04a |
| institution | OA Journals |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-bd44bd76aaef40c1bf1a167ae3aff04a2025-08-20T02:35:44ZengElsevierNeurobiology of Disease1095-953X2025-08-0121210699210.1016/j.nbd.2025.106992Sigma-1R–Pom121 axis preserves nuclear transport and integrity in poly-PR-induced C9orf72 ALSChun-Yu Lin0Hsuan-Cheng Wu1Ru-Huei Fu2Eddie Feng-Ju Weng3Wen-Chi Hsieh4Tsung-Ping Su5Hsiang-En Wu6Shao-Ming Wang7Neuroscience and Brain Disease Center, China Medical University, Taichung 404328, Taiwan; School of Medicine, College of Medicine, China Medical University, Taichung 404328, TaiwanNeuroscience and Brain Disease Center, China Medical University, Taichung 404328, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 404328, TaiwanGraduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 404328, Taiwan; Ph.D. Program for Aging, China Medical University, Taichung 404328, Taiwan; Translational Medicine Research Center, China Medical University Hospital, Taichung 40447, TaiwanNeuroscience and Brain Disease Center, China Medical University, Taichung 404328, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 404328, TaiwanNeuroscience and Brain Disease Center, China Medical University, Taichung 404328, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 404328, TaiwanCellular Pathobiology Section, Integrative Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, DHHS, 333 Cassell Drive, Baltimore, MD 21224, USACellular Pathobiology Section, Integrative Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, DHHS, 333 Cassell Drive, Baltimore, MD 21224, USANeuroscience and Brain Disease Center, China Medical University, Taichung 404328, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 404328, Taiwan; Corresponding author at: Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 404328, Taiwan.Nucleocytoplasmic transport disruption contributes to the pathogenesis of C9orf72-associated amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Among the dipeptide repeat proteins translated from G4C2-repeat RNA, poly-PR is particularly toxic, compromising nuclear envelope integrity and transport. Here, we revealed that poly-PR reduced expression of the nucleoporin Pom121 in NSC-34 cells and in an AAV-mediated poly-PR42 mouse model, resulting in cytoplasmic mislocalization of the neuroprotective transcription factor ATF3 and nuclear envelope damage. Pom121 overexpression restored nuclear ATF3 localization and alleviated poly-PR-induced toxicity. We further identified Sigma-1 receptor (Sigma-1R) as a stabilizer of Pom121 that preserved nuclear integrity and ATF3 function under oxidative stress. Overexpression of Sigma-1R, Pom121, or ATF3 rescued poly-PR-induced cytotoxicity. Our findings defined a protective Sigma-1R/Pom121/ATF3 axis and suggested this pathway as a therapeutic target in C9orf72-linked ALS.http://www.sciencedirect.com/science/article/pii/S0969996125002086Poly-PRC9orf72 ALSPom121Sigma-1RNucleocytoplasmic transportNuclear envelope integrity |
| spellingShingle | Chun-Yu Lin Hsuan-Cheng Wu Ru-Huei Fu Eddie Feng-Ju Weng Wen-Chi Hsieh Tsung-Ping Su Hsiang-En Wu Shao-Ming Wang Sigma-1R–Pom121 axis preserves nuclear transport and integrity in poly-PR-induced C9orf72 ALS Neurobiology of Disease Poly-PR C9orf72 ALS Pom121 Sigma-1R Nucleocytoplasmic transport Nuclear envelope integrity |
| title | Sigma-1R–Pom121 axis preserves nuclear transport and integrity in poly-PR-induced C9orf72 ALS |
| title_full | Sigma-1R–Pom121 axis preserves nuclear transport and integrity in poly-PR-induced C9orf72 ALS |
| title_fullStr | Sigma-1R–Pom121 axis preserves nuclear transport and integrity in poly-PR-induced C9orf72 ALS |
| title_full_unstemmed | Sigma-1R–Pom121 axis preserves nuclear transport and integrity in poly-PR-induced C9orf72 ALS |
| title_short | Sigma-1R–Pom121 axis preserves nuclear transport and integrity in poly-PR-induced C9orf72 ALS |
| title_sort | sigma 1r pom121 axis preserves nuclear transport and integrity in poly pr induced c9orf72 als |
| topic | Poly-PR C9orf72 ALS Pom121 Sigma-1R Nucleocytoplasmic transport Nuclear envelope integrity |
| url | http://www.sciencedirect.com/science/article/pii/S0969996125002086 |
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