Gaucher disease is an autosomal recessive metabolic disorder caused by mutations in GBA1, which encodes for the lysosomal hydrolase enzyme, β-glucocerebrosidase. The resulting misfolded protein can trigger endoplasmic reticulum stress and an unfolded protein response within the affected cells. The enzyme deficiency leads to accumulation of its substrates, glucosylceramide and glucosylsphingosine, within macrophage lysosomes and with prominent disease manifestations in macrophage rich tissues. Resultant lysosomal pathology and impaired autophagy leads to redox imbalance, mitochondrial dysfunction and intracellular oxidative stress. Here we have systematically examined a role for oxidative stress in individuals affected by Gaucher disease. We compared multiple oxidative stress biomarkers in plasma and red blood cell samples from patients who are currently untreated, with those who are stable on standard-of-care therapy, and with healthy controls. We found significant differences in key oxidative stress biomarkers in untreated patients compared to healthy control. In treated patients, results generally fell between the controls and the untreated patients. Interestingly, even asymptomatic and minimally symptomatic untreated patients had evidence of significant systemic oxidative stress. We conclude that underlying oxidative stress may contribute to Gaucher disease pathophysiology including long-term adverse outcomes such as Parkinsonism and malignancies. Therapies targeting oxidative stress may prove useful as adjuvant treatments for Gaucher disease and other lysosomal storage disorders.

高雪氏病是由GBA1突变引起的常染色体隐性代谢紊乱，它编码溶酶体水解酶β-葡萄糖脑苷脂酶。产生的错误折叠的蛋白质可触发内质网应激和受影响细胞内未折叠的蛋白质反应。酶缺乏导致其底物，糖基神经酰胺和糖基鞘氨醇在巨噬细胞溶酶体内积累，并在富含巨噬细胞的组织中具有明显的疾病表现。结果导致的溶酶体病理学和自噬受损导致氧化还原失衡，线粒体功能障碍和细胞内氧化应激。在这里，我们已经系统地检查了受高雪氏病影响的个体中氧化应激的作用。我们比较了目前未接受治疗的患者和依护理标准治疗稳定的患者血浆和红细胞样本中的多种氧化应激生物标记物，并控制健康。我们发现与健康对照组相比，未经治疗的患者在关键氧化应激生物标志物上存在显着差异。在接受治疗的患者中，结果通常介于对照组和未经治疗的患者之间。有趣的是，即使是无症状和无症状的未经治疗的患者，也有明显的全身性氧化应激的证据。我们得出结论，潜在的氧化应激可能有助于戈谢病的病理生理，包括帕金森氏病和恶性肿瘤等长期不良后果。针对氧化应激的疗法可能被证明可用于治疗高雪氏病和其他溶酶体贮积症。结果通常介于对照组和未经治疗的患者之间。有趣的是，即使是无症状和无症状的未经治疗的患者，也有明显的全身性氧化应激的证据。我们得出结论，潜在的氧化应激可能有助于戈谢病的病理生理，包括帕金森氏病和恶性肿瘤等长期不良后果。针对氧化应激的疗法可能被证明可用于治疗高雪氏病和其他溶酶体贮积症。结果通常介于对照组和未经治疗的患者之间。有趣的是，即使是无症状和无症状的未经治疗的患者，也有明显的全身性氧化应激的证据。我们得出结论，潜在的氧化应激可能有助于戈谢病的病理生理，包括帕金森氏病和恶性肿瘤等长期不良后果。针对氧化应激的疗法可能被证明可用于治疗高雪氏病和其他溶酶体贮积症。