Alpha-synuclein-glucocerebrosidase interactions in pharmacological Gaucher models: A biological link between Gaucher disease and parkinsonism
Alpha-synuclein-glucocerebrosidase interactions in pharmacological Gaucher models: A biological link between Gaucher disease and parkinsonism
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DOI：
10.1016/j.neuro.2009.06.009
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发表时间：
2009-11-01
期刊：
影响因子：
3.4
通讯作者：
Langston, J. William
中科院分区：
文献类型：
--
作者：
Manning-Bog, Amy B.;Schuele, Birgitt;Langston, J. William
越来越多的实验和临床文献表明戈谢病和帕金森病之间存在关联，这提高了趋同机制可能导致这些疾病的神经退行性变的可能性。本研究的目的是确定帕金森病发病机制中的关键蛋白α -突触核蛋白（α -syn）与糖脑苷（CC）分解代谢异常导致戈谢病的发展之间是否存在关系。我们用conduritol B环氧化物（CBE）抑制神经母细胞瘤细胞和小鼠中的葡萄糖脑苷酶（GCase），以测试GCase活性与α -syn之间是否存在生物学联系。暴露于CBE后，与对照体相比，CBE刺激的分化细胞中α -syn蛋白含量增加，α -syn mRNA含量无变化。在小鼠模型中，注射一次CBE后，也检测到神经α -syn水平升高。Western blot和共聚焦显微镜分析显示，CBE暴露后，正常的α -syn分布受到干扰，其在黑质细胞体和星形胶质细胞内明显积聚。这些发现提高了α -syn可能促进戈谢病中神经元功能障碍的级联事件的可能性，并且首次使用药理学模型暗示该蛋白可能是戈谢病和帕金森病之间的生物学交叉点。(C) 2009爱思唯尔公司版权所有。
A growing body of experimental and clinical literature indicates an association between Gaucher disease and parkinsonism, raising the possibility that convergent mechanisms may contribute to neurodegeneration in these disorders. The aim of this study was to determine whether there is a relationship between alpha-synuclein (alpha-syn), a key protein in Parkinson's disease pathogenesis, and abnormalities in glucocerebroside (CC) catabolism that lead to the development of Gaucher disease. We inhibited glucocerebrosidase (GCase) with conduritol B epoxide (CBE) in neuroblastoma cells and mice to test whether a biological link exists between GCase activity and alpha-syn. After CBE exposure, enhanced alpha-syn protein was detected in differentiated cells challenged with CBE as compared to vehicle, with no change in alpha-syn mRNA. In the mouse model, after one injection of CBE, elevated nigral alpha-syn levels were also detected. Analyses by Western blot and confocal microscopy revealed that normal alpha-syn distribution was perturbed after CBE exposure with its accumulation apparent within nigral cell bodies as well as astroglia. These findings raise the possibility that alpha-syn may contribute to the cascade of events that promote neuronal dysfunction in Gaucher disease and are the first to implicate this protein as a plausible biological intersection between Gaucher disease and parkinsonism using a pharmacological model. (C) 2009 Elsevier Inc. All rights reserved.