Kartha Reena V, Terluk Marcia R, Brown Roland, Travis Abigail, Mishra Usha R, Rudser Kyle, Lau Heather, Jarnes Jeanine R, Cloyd James C, Weinreb Neal J
Center for Orphan Drug Research, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, United States.
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, United States.
Mol Genet Metab Rep. 2020 Dec 9;25:100667. doi: 10.1016/j.ymgmr.2020.100667. eCollection 2020 Dec.
Gaucher disease is an autosomal recessive metabolic disorder caused by mutations in , 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.
戈谢病是一种常染色体隐性代谢紊乱疾病，由编码溶酶体水解酶β-葡萄糖脑苷脂酶的基因突变引起。由此产生的错误折叠蛋白可引发内质网应激以及受影响细胞内的未折叠蛋白反应。该酶的缺乏导致其底物葡糖神经酰胺和葡糖鞘氨醇在巨噬细胞溶酶体内蓄积，并在富含巨噬细胞的组织中出现明显的疾病表现。由此产生的溶酶体病理改变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。在此，我们系统地研究了氧化应激在戈谢病患者中的作用。我们比较了未经治疗的患者、接受标准治疗且病情稳定的患者以及健康对照者血浆和红细胞样本中的多种氧化应激生物标志物。我们发现，与健康对照相比，未经治疗的患者在关键氧化应激生物标志物方面存在显著差异。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，即使是无症状和症状轻微的未经治疗患者也有明显的全身氧化应激证据。我们得出结论，潜在的氧化应激可能导致戈谢病的病理生理过程，包括帕金森病和恶性肿瘤等长期不良后果。针对氧化应激的治疗可能被证明是戈谢病和其他溶酶体贮积症的有用辅助治疗方法。
