Wang, WeiNguyen, Linh T. T.Burlak, ChristopherChegini, FaribaGuo, FengChataway, TimJu, ShulinFisher, Oriana S.Miller, David W.Datta, DebajyotiWu, FangWu, Chun-XiangLanderu, AnuradhaWells, James A.Cookson, Mark R.Boxer, Matthew B.Thomas, Craig J.Gai, Wei PingRinge, DagmarPetsko, Gregory A.Hoang, Quyen Q.2017-06-272017-06-272016-08-23Wang, W., Nguyen, L. T. T., Burlak, C., Chegini, F., Guo, F., Chataway, T., … Hoang, Q. Q. (2016). Caspase-1 causes truncation and aggregation of the Parkinson’s disease-associated protein α-synuclein. Proceedings of the National Academy of Sciences of the United States of America, 113(34), 9587–9592. http://doi.org/10.1073/pnas.1610099113https://hdl.handle.net/1805/13175The aggregation of α-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.en-USPublisher PolicyParkinson's diseaseAggregationCaspaseInflammasomeSynucleinArticle