Caspase-1 causes truncation and aggregation of the Parkinson's disease-associated protein α-synuclein

Wei Wang, Linh Nguyen, Christopher Burlak, Fariba Chegini, Feng Guo, Timothy Chataway, Shulin Ju, Oriana Fisher, David Miller, Debajyoti Datta, Fang Wu, Chun-Xiang Wu, Anuradha Landeru, James Wells, Mark Cookson, Matthew Boxer, Craig Thomas, Wei-Ping Gai, Dagmar Ringe, Gregory PetskoQuyen Hoang

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    80 Citations (Scopus)

    Abstract

    The 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.

    Original languageEnglish
    Pages (from-to)9587-9592
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume113
    Issue number34
    DOIs
    Publication statusPublished - 23 Aug 2016

    Keywords

    • Aggregation
    • Caspase
    • Inflammasome
    • Parkinson's disease
    • Synuclein

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  • Cite this

    Wang, W., Nguyen, L., Burlak, C., Chegini, F., Guo, F., Chataway, T., Ju, S., Fisher, O., Miller, D., Datta, D., Wu, F., Wu, C-X., Landeru, A., Wells, J., Cookson, M., Boxer, M., Thomas, C., Gai, W-P., Ringe, D., ... Hoang, 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. https://doi.org/10.1073/pnas.1610099113