CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
Department of Neurobiology, Care Science and Society, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden.
Neurotherapeutics. 2021 Apr;18(2):1017-1038. doi: 10.1007/s13311-021-01022-9. Epub 2021 Apr 1.
Pridopidine is a selective Sigma-1 receptor (S1R) agonist in clinical development for Huntington disease (HD) and amyotrophic lateral sclerosis. S1R is a chaperone protein localized in mitochondria-associated endoplasmic reticulum (ER) membranes, a signaling platform that regulates Ca signaling, reactive oxygen species (ROS) and mitochondrial fission. Here, we investigate the protective effects of pridopidine on various mitochondrial functions in human and mouse HD models. Pridopidine effects on mitochondrial dynamics were assessed in primary neurons from YAC128 HD mice expressing the mutant human HTT gene. We observe that pridopidine prevents the disruption of mitochondria-ER contact sites and improves the co-localization of inositol 1,4,5-trisphosphate receptor (IPR) and its chaperone S1R with mitochondria in YAC128 neurons, leading to increased mitochondrial activity, elongation, and motility. Increased mitochondrial respiration is also observed in YAC128 neurons and in pridopidine-treated HD human neural stem cells (hNSCs). ROS levels were assessed after oxidative insult or S1R knockdown in pridopidine-treated YAC128 neurons, HD hNSCs, and human HD lymphoblasts. All HD models show increased ROS levels and deficient antioxidant response, which are efficiently rescued with pridopidine. Importantly, pridopidine treatment before HO-induced mitochondrial dysfunction and S1R presence are required for HD cytoprotection. YAC128 mice treated at early/pre-symptomatic age with pridopidine show significant improvement in motor coordination, indicating a delay in symptom onset. Additionally, in vivo pridopidine treatment reduces mitochondrial ROS levels by normalizing mitochondrial complex activity. In conclusion, S1R-mediated enhancement of mitochondrial function contributes to the neuroprotective effects of pridopidine, providing insight into its mechanism of action and therapeutic potential.
普里多宾是一种选择性西格玛-1 受体（S1R）激动剂，正在开发用于亨廷顿病（HD）和肌萎缩侧索硬化症（ALS）。S1R 是一种位于线粒体相关内质网（ER）膜中的伴侣蛋白，是一种调节 Ca 信号、活性氧（ROS）和线粒体裂变的信号平台。在这里，我们研究了普里多宾对人类和小鼠 HD 模型中各种线粒体功能的保护作用。在表达突变型人 HTT 基因的 YAC128 HD 小鼠的原代神经元中评估了普里多宾对线粒体动力学的影响。我们观察到，普里多宾可防止线粒体-ER 接触点的破坏，并改善 YAC128 神经元中肌醇 1,4,5-三磷酸受体（IPR）及其伴侣 S1R 与线粒体的共定位，从而增加线粒体活性、伸长和运动。还观察到 YAC128 神经元和用普里多宾处理的 HD 人神经干细胞（hNSC）中的线粒体呼吸增加。在经氧化应激或 S1R 敲低处理的普里多宾处理的 YAC128 神经元、HD hNSC 和人类 HD 淋巴母细胞中评估了 ROS 水平。所有 HD 模型均显示 ROS 水平升高和抗氧化反应不足，而用普里多宾有效地挽救了这些缺陷。重要的是，在 HO 诱导的线粒体功能障碍和 S1R 存在之前进行普里多宾治疗是 HD 细胞保护所必需的。用普里多宾治疗早期/无症状年龄的 YAC128 小鼠可显著改善运动协调能力，表明发病时间延迟。此外，体内普里多宾治疗通过使线粒体复合物活性正常化来降低线粒体 ROS 水平。总之，S1R 介导的线粒体功能增强有助于普里多宾的神经保护作用，为其作用机制和治疗潜力提供了深入了解。
