Cholesterol oxidation products are sensitive and specific blood-based biomarkers for Niemann-Pick C1 disease.
Cholesterol oxidation products are sensitive and specific blood-based biomarkers for Niemann-Pick C1 disease.
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DOI：
10.1126/scitranslmed.3001417
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发表时间：
2010-11-03
影响因子：
17.1
通讯作者：
Ory DS
中科院分区：
文献类型：
--
作者：
Porter FD;Scherrer DE;Lanier MH;Langmade SJ;Molugu V;Gale SE;Olzeski D;Sidhu R;Dietzen DJ;Fu R;Wassif CA;Yanjanin NM;Marso SP;House J;Vite C;Schaffer JE;Ory DS
C1型尼曼-皮克病（NPC 1）是一种罕见的进行性神经退行性疾病，其特征是内溶酶体胆固醇蓄积。先前的研究暗示氧化应激在NPC 1疾病发病机制中提出了胆固醇氧化产物的非酶促形成可以作为疾病生物标志物的可能性。我们测量了Npc 1 −/−小鼠模型的血浆和组织中的这些代谢物，发现Npc 1 −/−小鼠中升高的几种胆固醇氧化产物在症状发作前可检测到，并且与疾病进展相关。非酶促形成的胆固醇氧化产物在研究的所有人NPC 1受试者的血浆中类似地增加，并描绘了NPC 1疾病特异性的氧固醇谱。这种氧固醇谱也与疾病发作的年龄和疾病的严重程度相关。我们进一步表明，血浆氧固醇标志物减少，在NPC 1猫模型中建立的治疗干预。这些胆固醇氧化产物是NPC 1疾病的稳健的基于血液的生化标志物，其可能被证明对于这种疾病的诊断和治疗具有变革性，并且作为监测对治疗的反应的结果指标。
Niemann-Pick type C1 (NPC1) disease is a rare progressive neurodegenerative disorder characterized by endolysosomal cholesterol accumulation. Previous studies implicating oxidative stress in NPC1 disease pathogenesis raised the possibility that non-enzymatic 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 prior to the onset of symptoms, and were associated with disease progression. Non-enzymatically 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 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.
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影响因子：
9.3
作者：
Griffiths, William J.;Wang, Yuqin;Karu, Kersti;Samuel, Emmanuel;McDonnell, Shane;Hornshaw, Martin;Shackleton, Cedric
通讯作者：
Shackleton, Cedric
影响因子：
8
作者：
Ferderbar, S.;Pereira, E. C.;Abdalla, D. S. P.
通讯作者：
Abdalla, D. S. P.
影响因子：
3.5
作者：
Krakowiak, PA;Wassif, CA;Porter, FD
通讯作者：
Porter, FD
影响因子：
4.2
作者：
Brown, DE;Thrall, MA;Just, CA
通讯作者：
Just, CA
影响因子：
2
作者：
Jiang, Xuntian;Ory, Daniel S.;Han, Xianlin
通讯作者：
Han, Xianlin