Wu Hsuan-Cheng, Huang Teng-Wei, Weng Eddie Feng-Ju, Lin Chun-Yu, Su Tsung-Ping, Wu Hsiang-En, Wang Shao-Ming
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.
Neuroscience and Brain Disease Center, China Medical University, Taichung, 404328, Taiwan; Ph.D. Program for Aging, China Medical University, Taichung, 404328, Taiwan.
Redox Biol. 2025 Nov;87:103875. doi: 10.1016/j.redox.2025.103875. Epub 2025 Sep 20.
C9orf72-associated amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by the accumulation of toxic dipeptide repeat proteins (DPRs) generated from GC 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 (HO) 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.
与C9orf72相关的肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）的特征是由GC六核苷酸重复扩增产生的有毒二肽重复蛋白（DPRs）的积累。其中，富含精氨酸的多聚-PR（脯氨酸-精氨酸）种类是最具神经毒性的，通过非细胞自主机制引发胶质细胞活化和神经炎症。尽管越来越多的证据表明胶质细胞，特别是星形胶质细胞，参与了疾病进展，但将神经元衍生的多聚-PR与星形胶质细胞介导的氧化应激联系起来的分子途径仍知之甚少。我们证明，外源性多聚-PR通过激活IKK/IκB/NF-κB p65信号通路，在星形胶质细胞中诱导强烈的NOX4表达和过氧化氢（HO）产生。从机制上讲，多聚-PR促进p65的核转位并增强其与NOX4启动子的结合，从而放大星形胶质细胞的氧化应激。Sigma-1受体（Sigma-1R）是一种内质网驻留伴侣蛋白，其过表达通过与p65相互作用并阻断其核转位，显著减弱多聚-PR诱导的NOX4转录和活性氧（ROS）产生，而与上游p65磷酸化无关。值得注意的是，氯马斯汀是一种临床批准的Sigma-1R激动剂，通过破坏p65与NOX4启动子的结合来抑制星形胶质细胞的NOX4表达。在C9orf72 ALS小鼠模型中，Sigma-1R缺陷会加剧多聚-PR诱导的神经退行性变、星形胶质细胞增生和NOX4上调，而Sigma-1R充足则具有神经保护和抗炎作用。本研究确定Sigma-1R是非细胞自主多聚-PR毒性的关键调节因子，并将其激活确立为星形胶质细胞衍生氧化应激的有效抑制剂。我们的发现揭示了一种以前未被认识的驱动C9orf72 ALS发病机制的胶质细胞机制，并支持通过氯马斯汀激活Sigma-1R作为减轻神经炎症和疾病进展的有前景的治疗策略。
