2. Academic Validation
  3. Sigma-1 receptor counteracts non-cell-autonomous poly-PR-induced astrocytic oxidative stress in C9orf72 ALS

Sigma-1 receptor counteracts non-cell-autonomous poly-PR-induced astrocytic oxidative stress in C9orf72 ALS

  • Redox Biol. 2025 Sep 20:87:103875. doi: 10.1016/j.redox.2025.103875.
Hsuan-Cheng Wu 1,  Teng-Wei Huang 2,  Eddie Feng-Ju Weng 1,  Chun-Yu Lin 3,  Tsung-Ping Su 4,  Hsiang-En Wu 4,  Shao-Ming Wang 5
Affiliations

Affiliations

  • 1 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.
  • 2 Neuroscience and Brain Disease Center, China Medical University, Taichung, 404328, Taiwan; Ph.D. Program for Aging, China Medical University, Taichung, 404328, Taiwan.
  • 3 Neuroscience and Brain Disease Center, China Medical University, Taichung, 404328, Taiwan; School of Medicine, College of Medicine, China Medical University, Taichung, 404328, 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: 40992079 DOI: 10.1016/j.redox.2025.103875
Abstract

C9orf72-associated amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by the accumulation of toxic dipeptide repeat proteins (DPRs) generated from G4C2 hexanucleotide repeat expansions. Among these, the arginine-rich poly-PR (proline-arginine) species is the most neurotoxic, eliciting glial activation and neuroinflammation via non-cell-autonomous mechanisms. Although growing evidence implicates glial cells, particularly astrocytes, in disease progression, the molecular pathways linking neuron-derived poly-PR to astrocyte-mediated oxidative stress remain poorly understood. We demonstrate that exogenous poly-PR induces robust NOX4 expression and hydrogen peroxide (H2O2) production in astrocytes through activation of the IKK/IκB/NF-κB p65 signaling pathway. Mechanistically, poly-PR promotes nuclear translocation of p65 and enhances its binding to the NOX4 promoter, thereby amplifying astrocytic oxidative stress. Overexpression of the Sigma-1 receptor (Sigma-1R), an endoplasmic reticulum-resident chaperone, significantly attenuates poly-PR-induced NOX4 transcription and Reactive Oxygen Species (ROS) production by interacting with p65 and blocking its nuclear translocation, independently of upstream p65 phosphorylation. Notably, clemastine, a clinically approved Sigma-1R agonist, suppresses astrocytic NOX4 expression by disrupting p65 binding to the NOX4 promoter. In a mouse model of C9orf72 ALS, Sigma-1R deficiency exacerbates poly-PR-induced neurodegeneration, astrogliosis, and NOX4 upregulation, whereas Sigma-1R sufficiency confers neuroprotection and anti-inflammatory effects. This study identifies Sigma-1R as a critical modulator of non-cell-autonomous poly-PR toxicity and establishes its activation as a potent suppressor of astrocyte-derived oxidative stress. Our findings uncover a previously unrecognized glial mechanism driving C9orf72 ALS pathogenesis and support Sigma-1R activation, via clemastine, as a promising therapeutic strategy to mitigate neuroinflammation and disease progression.

Keywords

Astrocyte; C9orf72 ALS; NOX4; Non-cell-autonomous poly-PR; Sigma-1R.

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