Vascular and Genomic Center, Institute of ATPChanghua Christian Hospital, Changhua, Taiwan.
Center of Regenerative Medicine and Tissue Repair, Institute of ATPChanghua Christian Hospital, Changhua, Taiwan.
Sci Rep. 2024 Oct 29;14(1):25979. doi: 10.1038/s41598-024-77763-2.
This study investigated the therapeutic effects of astragaloside IV (AST) on spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), a neurodegenerative disorder. Human neuroblastoma SK-N-SH cells expressing mutant ataxin-3 protein with 78 CAG repeats (MJD78) were employed as an in vitro model. Protein expression analysis demonstrated that AST treatment reduced mutant ataxin-3 protein expression and aggregation by enhancing the autophagic process in MJD78 cells. Elevated oxidative stress levels in MJD78 cells were significantly reduced following AST treatment, which also enhanced antioxidant capacity, as evidenced by flow cytometry and antioxidant enzyme activity assays. Furthermore, AST treatment ameliorated mitochondrial dysfunction in MJD78 cells, including improvements in mitochondrial membrane potential, respiration, and mitochondrial dynamics. In conclusion, AST administration increased antioxidant capacity, reduced both cellular and mitochondrial oxidative stress, and improved mitochondrial quality control processes through fusion, fission, and autophagy. These mechanisms collectively reduced intracellular mutant ataxin-3 protein aggregation, thereby achieving therapeutic efficacy in the SCA3 model.
本研究探讨了黄芪甲苷（AST）对脊髓小脑共济失调 3 型（SCA3），也称为 Machado-Joseph 病（MJD）的治疗作用，MJD 是一种神经退行性疾病。表达具有 78 个 CAG 重复突变的人神经母细胞瘤 SK-N-SH 细胞（MJD78）被用作体外模型。蛋白表达分析表明，AST 治疗通过增强 MJD78 细胞的自噬过程，降低了突变型 ataxin-3 蛋白的表达和聚集。AST 处理后，MJD78 细胞中升高的氧化应激水平显著降低，这也通过流式细胞术和抗氧化酶活性测定证实了抗氧化能力的增强。此外，AST 治疗改善了 MJD78 细胞中的线粒体功能障碍，包括线粒体膜电位、呼吸和线粒体动力学的改善。总之，AST 给药增加了抗氧化能力，减少了细胞和线粒体氧化应激，并通过融合、裂变和自噬改善了线粒体质量控制过程。这些机制共同减少了细胞内突变型 ataxin-3 蛋白的聚集，从而在 SCA3 模型中实现了治疗效果。
