Sigma-1 Receptor Mitigates Poly-GR-Associated Redox Dysregulation by Restoring NRF2/HO1 Signaling in C9orf72-Associated ALS.

Chao-Yi Tsai, Hsuan-Cheng Wu, Tsung-Ping Su, Eddie Feng-Ju Weng, Shao-Ming Wang

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Article in Neuromolecular medicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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5 authors.

Chao-Yi TsaiNeuroscience and Brain Disease Center, China Medical University, Taichung, 404328, Taiwan.

Hsuan-Cheng WuNeuroscience and Brain Disease Center, China Medical University, Taichung, 404328, Taiwan.

Tsung-Ping SuCellular Pathobiology Section, Integrative Neuroscience Research Branch, DHHS, Intramural Research Program, National Institute On Drug Abuse, National Institutes of Health, 333 Cassell Drive, Baltimore, MD, 21224, USA.

Eddie Feng-Ju WengNeuroscience and Brain Disease Center, China Medical University, Taichung, 404328, Taiwan. eddieweng@mail.cmu.edu.tw.

Shao-Ming WangNeuroscience and Brain Disease Center, China Medical University, Taichung, 404328, Taiwan. wangs@mail.cmu.edu.tw.ORCID https://orcid.org/0000-0003-1479-9100

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Hexanucleotide GGGGCC repeat expansions in C9orf72 produce arginine-rich dipeptide repeat proteins, including poly-GR and poly-PR, that contribute to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Although poly-GR has been linked to oxidative stress and mitochondrial dysfunction, the mechanisms that determine whether antioxidant defenses are preserved or suppressed in poly-GR-expressing motor neurons remain incompletely understood. Here, we investigated whether Sigma-1 receptor (Sigma-1R) modulates poly-GR-associated redox dysregulation in cellular and mouse models. In NSC34 cells, both EGFP-PR

Indexed as

Amyotrophic Lateral SclerosisC9orf72 ProteinHeme Oxygenase-1Membrane ProteinsNF-E2-Related Factor 2Receptors, sigmaAnimalsCell LineFluvoxamineHumansMaleMiceMice, Inbred C57BLMice, TransgenicMorpholinesMotor Neurons2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylateC9orf72 ProteinC9orf72 protein, humanFluvoxamineHeme Oxygenase-1Hmox1 protein, mouseMembrane ProteinsMorpholinesNfe2l2 protein, mouseNF-E2-Related Factor 2Reactive Oxygen SpeciesReceptors, sigmaSigma-1 ReceptorC9orf72 ALSNRF2Poly-GRROSSigma-1R

Identifiers

PMID42860504

DOI10.1007/s12017-026-08951-8

PMCPMC13654898

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