Elevated levels of oxidized cholesterol metabolites in Lewy body disease brains accelerate α-synuclein fibrilization
Elevated levels of oxidized cholesterol metabolites in Lewy body disease brains accelerate α-synuclein fibrilization
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DOI：
10.1038/nchembio782
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发表时间：
2006-05-01
影响因子：
14.8
通讯作者：
Kelly, JW
中科院分区：
文献类型：
--
作者：
Bosco, DA;Fowler, DM;Kelly, JW
氧化应激、炎症和α-突触核蛋白过表达（1）会增加发生α-突触核蛋白病神经退行性疾病的风险，包括帕金森病和路易体痴呆（2）。多巴胺能神经元在这些疾病中发生变性，并且特别容易受到氧化应激的影响，因为多巴胺代谢本身会产生活性氧（3）。α-突触核蛋白作为淀粉样纤维或路易体的神经元内沉积是这些疾病的标志（2）。在此，我们证明，来自活性氧的氧化胆固醇代谢产物的浓度升高与路易体痴呆的个体的皮质相对于那些年龄匹配的控制，我们表明，这些代谢产物加速α-突触核蛋白在体外聚集。在过表达α-突触核蛋白的多巴胺能细胞系中也观察到这些细胞毒性胆固醇代谢产物的产生增加（4）。通过扩展，这些数据导致氧化应激产生胆固醇醛，使α-突触核蛋白聚集，导致病理循环的假设。
Oxidative stress, inflammation and alpha-synuclein overexpression(1) confer risk for development of alpha-synucleinopathies neurodegenerative diseases that include Parkinson disease and Lewy body dementia(2). Dopaminergic neurons undergo degeneration in these diseases and are particularly susceptible to oxidative stress because dopamine metabolism itself creates reactive oxygen species(3). Intraneuronal deposition of alpha-synuclein as amyloid fibrils or Lewy bodies is the hallmark of these diseases(2). Herein, we demonstrate that concentrations of oxidative cholesterol metabolites derived from reactive oxygen species are elevated in the cortices of individuals with Lewy body dementia relative to those of age-matched controls, and we show that these metabolites accelerate alpha-synuclein aggregation in vitro. The increase in the production of these cytotoxic cholesterol metabolites is also observed in a dopaminergic cell line that overexpresses alpha-synuclein(4). By extension, these data lead to the hypothesis that oxidative stress produces cholesterol aldehydes that enable alpha-synuclein aggregation, leading to a pathologic cycle.