Studies of lipopolysaccharide effects on the induction of α-synuclein pathology by exogenous fibrils in transgenic mice.
Studies of lipopolysaccharide effects on the induction of α-synuclein pathology by exogenous fibrils in transgenic mice.
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DOI：
10.1186/s13024-015-0029-4
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发表时间：
2015-07-30
影响因子：
15.1
通讯作者：
Giasson BI
中科院分区：
文献类型：
--
作者：
Rutherford NJ;Sacino AN;Brooks M;Ceballos-Diaz C;Ladd TB;Howard JK;Golde TE;Giasson BI
帕金森病（PD）是一种进行性神经退行性疾病，其病理特征是黑质多巴胺能神经元丢失，α-突触核蛋白（αS）聚集，神经炎症。实验研究表明，脑内注射重组原纤维αS，特别是在αS转基因小鼠模型中，可诱导αS包涵病理的形成和扩散。然而，报道这一现象的研究并没有考虑到在大肠杆菌产生的注射αS中存在脂多糖（LPS），这是一个潜在的混淆。本研究的目的是建立一种去除LPS污染的方法，并研究含有αS的LPS和高纯度αS LPS诱导的病理差异。通过在纯化过程中添加一个阳离子交换步骤，我们能够从αS制备中去除> 99.5%的LPS污染。注射含有LPS的αS或LPS纯化的αS原纤维诱导的αS病理表现出相似的分布规律；然而，注射含有较高水平LPS的αS的小鼠，其向皮质的扩散较少。先前报道，注射αS原纤维可诱导星形胶质细胞形成，αS原纤维经阳离子交换纯化或不经阳离子交换纯化后，小鼠星形胶质细胞内均存在αS包涵体。此外，我们在两组小鼠的室管膜细胞中发现了αS病理的存在，这表明αS病理模型涉及一种新的传播机制。本文的在线版本（doi:10.1186/s13024-015-0029-4）包含补充资料，仅供授权用户使用。
Parkinson’s disease (PD) is a progressive neurodegenerative disorder that is pathologically characterized by loss of dopaminergic neurons from the substantia nigra, the presence of aggregated α-synuclein (αS) and evidence of neuroinflammation. Experimental studies have shown that the cerebral injection of recombinant fibrillar αS, especially in αS transgenic mouse models, can induce the formation and spread of αS inclusion pathology. However, studies reporting this phenomenon did not consider the presence of lipopolysaccharide (LPS) in the injected αS, produced in E. coli, as a potential confound. The objectives of this study are to develop a method to remove the LPS contamination and investigate the differences in pathologies induced by αS containing LPS or αS highly purified of LPS. We were able to remove >99.5 % of the LPS contamination from the αS preparations through the addition of a cation exchange step during purification. The αS pathology induced by injection of fibrils produced from αS containing LPS or purified of LPS, showed a similar distribution pattern; however, there was less spread into the cortex of the mice injected with αS containing higher levels of LPS. As previously reported, injection of αS fibrils could induce astrogliosis, and αS inclusions were present within astrocytes in mice injected with fibrils comprised of αS with or without cation exchange purification. Furthermore, we identified the presence of αS pathology in ependymal cells in both groups of mice, which suggests the involvement of a novel mechanism for spread in this model of αS pathology. The online version of this article (doi:10.1186/s13024-015-0029-4) contains supplementary material, which is available to authorized users.