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 journalArticlepeer-review

88 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

Bibliographical note

Funding Information:
We thank S. Lindquist for the yeast expression vectors of aSyn, and Z. Y .Z. Zhang and L. Chen for their generous support and access to the Chemical Genomics Core Facility at Indiana University. Q.Q.H., D.R., and G.A.P. were supported through a Community Fast Track grant from the Michael J. Fox Foundation. Q.Q.H. was also supported by National Institutes of Health Grants 1R21NS079881-01 and 5R01GM111639, an Indiana University School of Medicine Biomedical Research Grant, and an Indiana University-Purdue University Indianapolis Research Support Funds Grant. D.R. and G.A.P. also acknowledge support from the Fidelity Biosciences Research Initiative (with much useful discussion from Dr. S. Weninger) and early support from the Ellison Medical Foundation and the McKnight Endowment for Neuroscience. M.B.B. and C.J.T. acknowledge support from the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research and the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. This research was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health.

Keywords

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

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