Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
Sci Transl Med. 2010 Nov 3;2(56):56ra81. doi: 10.1126/scitranslmed.3001417.
Niemann-Pick type C1 (NPC1) disease is a rare progressive neurodegenerative disorder characterized by accumulation of cholesterol in the endolysosomes. Previous studies implicating oxidative stress in NPC1 disease pathogenesis raised the possibility that nonenzymatic formation of cholesterol oxidation products could serve as disease biomarkers. We measured these metabolites in the plasma and tissues of the Npc1(-/-) mouse model and found several cholesterol oxidation products that were elevated in Npc1(-/-) mice, were detectable before the onset of symptoms, and were associated with disease progression. Nonenzymatically formed cholesterol oxidation products were similarly increased in the plasma of all human NPC1 subjects studied and delineated an oxysterol profile specific for NPC1 disease. This oxysterol profile also correlated with the age of disease onset and disease severity. We further show that the plasma oxysterol markers decreased in response to an established therapeutic intervention in the NPC1 feline model. These cholesterol oxidation products are robust blood-based biochemical markers for NPC1 disease that may prove transformative for diagnosis and treatment of this disorder, and as outcome measures to monitor response to therapy.
尼曼-匹克 C1 型（NPC1）病是一种罕见的进行性神经退行性疾病，其特征是胆固醇在内溶酶体中积累。先前的研究表明氧化应激与 NPC1 病的发病机制有关，这使得非酶形成的胆固醇氧化产物有可能成为疾病的生物标志物。我们在 NPC1（-/-）小鼠模型的血浆和组织中测量了这些代谢物，发现了几种在 NPC1（-/-）小鼠中升高的胆固醇氧化产物，这些产物在症状出现之前即可检测到，并且与疾病进展相关。在所有研究的 NPC1 患者的血浆中，非酶形成的胆固醇氧化产物也同样增加，并描绘出一种特定于 NPC1 疾病的氧化固醇特征。该氧化固醇特征还与疾病发病年龄和严重程度相关。我们进一步表明，在 NPC1 猫模型中，经已确立的治疗干预后，血浆中的氧化固醇标志物降低。这些胆固醇氧化产物是 NPC1 疾病的可靠血液生化标志物，可能为该疾病的诊断和治疗带来变革，并作为监测治疗反应的疗效指标。
