美国哈佛医学院Fumito Ichinose小组的最新研究探明了缺氧改善帕金森病小鼠模型的神经变性和运动障碍。2025年8月6日出版的《自然—神经科学》杂志发表了这项成果。

在这里，课题组研究人员报告了在小鼠的纹状体内注射α-syn预形成原纤维（PFFs）导致神经变性和运动障碍，这可以通过持续暴露于11%的氧气来预防。其中，PFF诱导的α-syn聚集导致呼吸21%氧小鼠SNpc脑组织高氧、脂质过氧化和DA神经变性，而呼吸11%氧小鼠则无此现象。在秀丽隐杆线虫中也观察到这种缺氧的神经保护作用。

此外，注射PFF后6周开始缺氧可逆转运动功能障碍并阻止进一步的DA神经退行性变。这些结果表明，即使在症状出现和神经病理改变后，缺氧也可能在PD中α-syn聚集的下游发挥神经保护作用。

据了解，帕金森病（PD）以黑质致密部（SNpc）多巴胺能（DA）神经元α-突触核蛋白（α-syn）缺失和线粒体功能障碍为特征。PD患者在高海拔地区症状有所改善；慢性缺氧可防止线粒体复合体I缺乏症小鼠发生Leigh样脑病。

附：英文原文

Title: Hypoxia ameliorates neurodegeneration and movement disorder in a mouse model of Parkinson’s disease

Author: Marutani, Eizo, Miranda, Maria, Durham, Timothy J., Kim, Sharon H., Russell, Dreson L., Wiesenthal, Presli P., Lichtenegger, Paul, Menard, Marissa A., Brzozowski, Charlotte F., Li, Haobo, Ruvkun, Gary, Meisel, Joshua D., Volpicelli-Daley, Laura, Mootha, Vamsi K., Ichinose, Fumito

Issue&Volume: 2025-08-06

Abstract: Parkinson’s disease (PD) is characterized by inclusions of α-synuclein (α-syn) and mitochondrial dysfunction in dopaminergic (DA) neurons of the substantia nigra pars compacta (SNpc). Patients with PD anecdotally experience symptom improvement at high altitude; chronic hypoxia prevents the development of Leigh-like brain disease in mice with mitochondrial complex I deficiency. Here we report that intrastriatal injection of α-syn preformed fibrils (PFFs) in mice resulted in neurodegeneration and movement disorder, which were prevented by continuous exposure to 11% oxygen. Specifically, PFF-induced α-syn aggregation resulted in brain tissue hyperoxia, lipid peroxidation and DA neurodegeneration in the SNpc of mice breathing 21% oxygen, but not in those breathing 11% oxygen. This neuroprotective effect of hypoxia was also observed in Caenorhabditis elegans. Moreover, initiating hypoxia 6 weeks after PFF injection reversed motor dysfunction and halted further DA neurodegeneration. These results suggest that hypoxia may have neuroprotective effects downstream of α-syn aggregation in PD, even after symptom onset and neuropathological changes.

DOI: 10.1038/s41593-025-02010-4

Source: https://www.nature.com/articles/s41593-025-02010-4