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Proc Natl Acad Sci U S A. 2016 Aug 23;113(34):9587-92. doi: 10.1073/pnas.1610099113. Epub 2016 Aug 1.

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

Author information

1
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202;
2
Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN 55455;
3
Department of Human Physiology, Center for Neuroscience, Flinders University, Adelaide 5001, Australia;
4
Department of Chemistry, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA 02454; Department of Biochemistry, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA 02454;
5
Laboratory of Neurogenetics, National Institutes of Health, Bethesda, MD 20892;
6
Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143;
7
Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143;
8
Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892;
9
Department of Chemistry, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA 02454; Department of Biochemistry, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA 02454; Department of Neurology, Harvard Medical School, Cambridge, MA 02139; Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02116;
10
Department of Chemistry, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA 02454; Department of Biochemistry, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA 02454; Department of Neurology, Harvard Medical School, Cambridge, MA 02139; Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02116; gpetsko@med.cornell.edu qqhoang@iu.edu.
11
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202; Department of Neurology, Indiana University School of Medicine, Indianapolis, IN 46202 gpetsko@med.cornell.edu qqhoang@iu.edu.

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.

KEYWORDS:

Parkinson's disease; aggregation; caspase; inflammasome; synuclein

PMID:
27482083
PMCID:
PMC5003239
DOI:
10.1073/pnas.1610099113
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

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