α-synuclein expression modulates microglial activation phenotype
α-synuclein expression modulates microglial activation phenotype
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DOI：
10.1523/jneurosci.1799-06.2006
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发表时间：
2006-10-11
影响因子：
5.3
通讯作者：
Combs, Colin K.
中科院分区：
文献类型：
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作者：
Austin, Susan A.;Floden, Angela M.;Combs, Colin K.
最近的帕金森氏病研究集中在了解细胞溶质蛋白，α-突触核蛋白的功能，及其对疾病机制的贡献。在神经元内，假设α-突触核蛋白在调节突触可塑性、囊泡释放和运输中具有作用。与此相反，胶质细胞表达的α-突触核蛋白仍然很少描述。在这里，我们研究的后果损失的α-突触核蛋白表达的小胶质细胞激活。使用出生后的脑源性培养系统，我们定义了野生型和敲除α-突触核蛋白小鼠（Scna（-/-））的小胶质细胞的表型。与野生型细胞相比，Scna（-/-）小胶质细胞表现出基础增加的反应表型，刺激后反应表型加重。与野生型相比，它们还表现出显着的形态学差异，表现为充满空泡样结构的大的分枝细胞。这与Scna（-/）-细胞中活化标志物CD 68和β 1整联蛋白的蛋白水平增加相对应。更重要的是，与野生型相比，Scna（-/-）小胶质细胞在刺激后分泌升高水平的促炎细胞因子TNF α（肿瘤坏死因子α）和IL-6（白细胞介素-6）。然而，尽管Scna（-/-）细胞具有反应性表型，但其吞噬能力受损。我们首次证明α-突触核蛋白在调节小胶质细胞激活状态中起着关键作用。我们认为，改变小胶质细胞α-突触核蛋白的表达将影响他们的表型已经在神经元中证明。这对于小胶质细胞对疾病的病理生理学的贡献具有直接影响，特别是在与改变的α-突触核蛋白表达相关的家族性病例中。
Recent Parkinson's disease research has focused on understanding the function of the cytosolic protein, alpha-synuclein, and its contribution to disease mechanisms. Within neurons, alpha-synuclein is hypothesized to have a role in regulating synaptic plasticity, vesicle release, and trafficking. In contrast, glial-expressed alpha-synuclein remains poorly described. Here, we examine the consequence of a loss of alpha-synuclein expression on microglial activation. Using a postnatal brain-derived culture system, we defined the phenotype of microglia from wildtype and knock-out alpha-synuclein mice (Scna(-/-)). Scna(-/-)microglia displayed a basally increased reactive phenotype compared with the wild-type cells and an exacerbated reactive phenotype after stimulation. They also exhibited dramatic morphologic differences compared with wild-type, presenting as large, ramified cells filled with vacuole-like structures. This corresponded with increased protein levels of activation markers, CD68 and beta 1 integrin, in the Scna(-/)-cells. More importantly, Scna(-/-)microglia, after stimulation, secreted elevated levels of proinflammatory cytokines, TNF alpha (tumor necrosis factor alpha) and IL-6 (interleukin-6), compared with wild type. However, despite the reactive phenotype, Scna(-/-)cells had impaired phagocytic ability. We demonstrate for the first time that alpha-synuclein plays a critical role in modulating microglial activation state. We suggest that altered microglial alpha-synuclein expression will affect their phenotype as has already been demonstrated in neurons. This has direct ramifications for the contribution of microglia to the pathophysiology of disease, particularly in familial cases linked to altered alpha-synuclein expression.