Sigma-1R-Pom121 axis preserves nuclear transport and integrity in poly-PR-induced C9orf72 ALS

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

doi:10.1016/j.nbd.2025.106992

Sigma-1R-Pom121 axis preserves nuclear transport and integrity in poly-PR-induced C9orf72 ALS

Neurobiol Dis. 2025 Aug:212:106992. doi: 10.1016/j.nbd.2025.106992. Epub 2025 Jun 5.

Authors

Chun-Yu Lin¹, Hsuan-Cheng Wu², Ru-Huei Fu³, Eddie Feng-Ju Weng², Wen-Chi Hsieh², Tsung-Ping Su⁴, Hsiang-En Wu⁴, Shao-Ming Wang⁵

Affiliations

¹ Neuroscience and Brain Disease Center, China Medical University, Taichung 404328, Taiwan; School of Medicine, College of Medicine, China Medical University, Taichung 404328, Taiwan.
² Neuroscience and Brain Disease Center, China Medical University, Taichung 404328, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 404328, Taiwan.
³ Graduate 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, Taiwan.
⁴ Cellular 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, USA.
⁵ Neuroscience and Brain Disease Center, China Medical University, Taichung 404328, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 404328, Taiwan. Electronic address: wangs@mail.cmu.edu.tw.

PMID: 40480424
DOI: 10.1016/j.nbd.2025.106992

Abstract

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.

Keywords: Atf3; C9orf72 ALS; Nuclear envelope integrity; Nucleocytoplasmic transport; Poly-PR; Pom121; Sigma-1R.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Activating Transcription Factor 3 / metabolism
Active Transport, Cell Nucleus* / physiology
Amyotrophic Lateral Sclerosis* / genetics
Amyotrophic Lateral Sclerosis* / metabolism
Amyotrophic Lateral Sclerosis* / pathology
Animals
C9orf72 Protein* / genetics
C9orf72 Protein* / metabolism
Disease Models, Animal
Humans
Mice
Mice, Transgenic
Nuclear Pore Complex Proteins* / genetics
Nuclear Pore Complex Proteins* / metabolism
Receptors, sigma* / genetics
Receptors, sigma* / metabolism
Sigma-1 Receptor

Substances

Receptors, sigma
C9orf72 Protein
Sigma-1 Receptor
Nuclear Pore Complex Proteins
Activating Transcription Factor 3
C9orf72 protein, human