Caspase-1 causes truncation and aggregation of the Parkinson's disease-associated protein α-synuclein
Caspase-1 causes truncation and aggregation of the Parkinson's disease-associated protein α-synuclein
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DOI：
10.1073/pnas.1610099113
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发表时间：
2016-08-23
影响因子：
11.1
通讯作者：
Hoang, Quyen Q.
中科院分区：
文献类型：
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作者：
Wang, Wei;Nguyen, Linh T. T.;Hoang, Quyen Q.
α-突触核蛋白(ASyn)的聚集导致路易小体的形成是帕金森病(PD)的重要病理特征。ASyn中罕见的家族性PD相关突变使其易于聚集；然而，携带野生型(WT)aSyn的PD患者也在路易体中聚集了aSyn。WT aSyn聚集的机制尚不清楚。在这里，我们报告炎症可以在导致WT aSyn聚集中发挥作用。我们发现，在PD的神经细胞模型中，用已知刺激激活炎症体会导致aSyn的聚集。在帕金森病脑的路易小体中发现，截短的aSyn富含不可溶的聚集体。通过化学抑制或用shRNA的基因敲除来抑制炎症体酶caspase-1可减弱aSyn截断。体外鉴定证实，caspase-1直接切割aSyn，产生高度聚集的物种。截断诱导的aSyn聚集对神经元培养有毒性，shRNA或特定的化学抑制剂抑制caspase-1可提高神经元PD细胞模型的存活率。这项研究为炎症在aSyn聚集中的作用提供了分子联系，可能也在散发性帕金森病的发病机制中起到了作用。
The aggregation of alpha-synuclein (aSyn) leading to the formation of Lewy bodies is the defining pathological hallmark of Parkinson's disease (PD). Rare familial PD-associated mutations in aSyn render it aggregation-prone; however, PD patients carrying wild type (WT) aSyn also have aggregated aSyn in Lewy bodies. The mechanisms by which WT aSyn aggregates are unclear. Here, we report that inflammation can play a role in causing the aggregation of WT aSyn. We show that activation of the inflammasome with known stimuli results in the aggregation of aSyn in a neuronal cell model of PD. The insoluble aggregates are enriched with truncated aSyn as found in Lewy bodies of the PD brain. Inhibition of the inflammasome enzyme caspase-1 by chemical inhibition or genetic knockdown with shRNA abated aSyn truncation. In vitro characterization confirmed that caspase-1 directly cleaves aSyn, generating a highly aggregation-prone species. The truncation-induced aggregation of aSyn is toxic to neuronal culture, and inhibition of caspase-1 by shRNA or a specific chemical inhibitor improved the survival of a neuronal PD cell model. This study provides a molecular link for the role of inflammation in aSyn aggregation, and perhaps in the pathogenesis of sporadic PD as well.