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

Wei Wang, Linh T.T. Nguyen, Christopher Burlak, Fariba Chegini, Feng Guo, Tim Chataway, Shulin Ju, Oriana S. Fisher, David W. Miller, Debajyoti Datta, Fang Wu, Chun Xiang Wu, Anuradha Landeru, James A. Wells, Mark R. Cookson, Matthew B. Boxer, Craig J. Thomas, Wei Ping Gai, Dagmar Ringe, Gregory A. PetskoQuyen Q. Hoang

Research output: Contribution to journalArticle

70 Scopus citations

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 (US)
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
StatePublished - Aug 23 2016

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Keywords

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

ASJC Scopus subject areas

  • General

Cite this

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