CABIMER-Andalusian Center for Molecular Biology and Regenerative Medicine, Consejo Superior de Investigaciones Científicos, University of Seville-UPO-Junta de Andalucia, Seville, Spain.
PLoS One. 2010 Oct 26;5(10):e13481. doi: 10.1371/journal.pone.0013481.
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized pathologically by the presence in the brain of intracellular protein inclusions highly enriched in aggregated alpha-synuclein (α-Syn). Although it has been established that progression of the disease is accompanied by sustained activation of microglia, the underlying molecules and factors involved in these immune-triggered mechanisms remain largely unexplored. Lately, accumulating evidence has shown the presence of extracellular α-Syn both in its aggregated and monomeric forms in cerebrospinal fluid and blood plasma. However, the effect of extracellular α-Syn on cellular activation and immune mediators, as well as the impact of familial PD-linked α-Syn mutants on this stimulation, are still largely unknown.
In this work, we have compared the activation profiles of non-aggregated, extracellular wild-type and PD-linked mutant α-Syn variants on primary glial and microglial cell cultures. After stimulation of cells with α-Syn, we measured the release of Th1- and Th2- type cytokines as well as IP-10/CXCL10, RANTES/CCL5, MCP-1/CCL2 and MIP-1α/CCL3 chemokines. Contrary to what had been observed using cell lines or for the case of aggregated α-Syn, we found strong differences in the immune response generated by wild-type α-Syn and the familial PD mutants (A30P, E46K and A53T).
These findings might contribute to explain the differences in the onset and progression of this highly debilitating disease, which could be of value in the development of rational approaches towards effective control of immune responses that are associated with PD.
帕金森病（PD）是一种进行性神经退行性疾病，其病理学特征是大脑中富含聚集态α-突触核蛋白（α-Syn）的细胞内蛋白包涵体的存在。虽然已经确定疾病的进展伴随着小胶质细胞的持续激活，但这些免疫触发机制所涉及的潜在分子和因素在很大程度上仍未得到探索。最近，越来越多的证据表明，细胞外α-Syn 以其聚集态和单体形式存在于脑脊液和血浆中。然而，细胞外 α-Syn 对细胞激活和免疫介质的影响，以及家族性 PD 相关 α-Syn 突变体对这种刺激的影响，在很大程度上仍然未知。
在这项工作中，我们比较了非聚集态、细胞外野生型和 PD 相关突变体α-Syn 变体对原代神经胶质细胞和小胶质细胞培养物的激活谱。在用 α-Syn 刺激细胞后，我们测量了 Th1 和 Th2 型细胞因子以及 IP-10/CXCL10、RANTES/CCL5、MCP-1/CCL2 和 MIP-1α/CCL3 趋化因子的释放。与使用细胞系或聚集态 α-Syn 观察到的情况相反，我们发现野生型 α-Syn 和家族性 PD 突变体（A30P、E46K 和 A53T）引起的免疫反应存在很大差异。
这些发现可能有助于解释这种高度致残疾病的发病和进展的差异，这对于开发合理的方法来有效控制与 PD 相关的免疫反应可能具有重要价值。
