Related Experiment Video
Updated: Jun 12, 2025
08:53
Assay to Measure Nucleocytoplasmic Transport in Real Time within Motor Neuron-like NSC-34 Cells
Published on: May 16, 2017
8.7K
Sigma-1R-Pom121 axis preserves nuclear transport and integrity in poly-PR-induced C9orf72 ALS
Chun-Yu Lin1, Hsuan-Cheng Wu2, Ru-Huei Fu3
1Neuroscience and Brain Disease Center, China Medical University, Taichung 404328, Taiwan; School of Medicine, College of Medicine, China Medical University, Taichung 404328, Taiwan.
Neurobiology of Disease
|June 6, 2025
Summary
Poly-PR protein disrupts nucleocytoplasmic transport in C9orf72-associated ALS and FTD. Targeting the Sigma-1R/Pom121/ATF3 pathway may offer therapeutic benefits for these neurodegenerative diseases.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Nucleocytoplasmic transport is crucial for neuronal function.
- Disruptions in this transport are implicated in C9orf72-associated amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
- Dipeptide repeat proteins, like poly-PR, are toxic and compromise nuclear integrity.
Purpose of the Study:
- To investigate the role of poly-PR in nucleocytoplasmic transport disruption.
- To identify molecular mechanisms and potential therapeutic targets for C9orf72-linked neurodegenerative diseases.
Main Methods:
- Used NSC-34 cells and an AAV-mediated poly-PR mouse model.
- Assessed the expression of nucleoporin Pom121 and the localization of transcription factor ATF3.
- Investigated the role of Sigma-1 receptor (Sigma-1R) in stabilizing Pom121.
Main Results:
- Poly-PR reduced Pom121 expression, leading to cytoplasmic ATF3 mislocalization and nuclear envelope damage.
- Pom121 overexpression restored nuclear ATF3 localization and reduced poly-PR toxicity.
- Sigma-1R stabilized Pom121, preserving nuclear integrity and ATF3 function under oxidative stress.
- Overexpression of Sigma-1R, Pom121, or ATF3 rescued poly-PR-induced cytotoxicity.
Conclusions:
- A protective Sigma-1R/Pom121/ATF3 axis was identified.
- This pathway represents a potential therapeutic target for C9orf72-linked ALS and FTD.
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