title: Caspase-1 causes truncation and aggregation of the Parkinson's disease-associated protein α-synuclein.
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.
authors.affiliation: 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;
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: 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;
authors.forename: Linh T T
authors.initials: LT
authors.lastname: Nguyen
authors.affiliation: Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN 55455;
authors.forename: Christopher
authors.initials: C
authors.lastname: Burlak
authors.affiliation: Department of Human Physiology, Center for Neuroscience, Flinders University, Adelaide 5001, Australia;
authors.forename: Fariba
authors.initials: F
authors.lastname: Chegini
authors.affiliation: Department of Human Physiology, Center for Neuroscience, Flinders University, Adelaide 5001, Australia;
authors.forename: Feng
authors.initials: F
authors.lastname: Guo
authors.affiliation: Department of Human Physiology, Center for Neuroscience, Flinders University, Adelaide 5001, Australia;
authors.forename: Tim
authors.initials: T
authors.lastname: Chataway
authors.affiliation: 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;
authors.forename: Shulin
authors.initials: S
authors.lastname: Ju
authors.affiliation: 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;
authors.forename: Oriana S
authors.initials: OS
authors.lastname: Fisher
authors.affiliation: Laboratory of Neurogenetics, National Institutes of Health, Bethesda, MD 20892;
authors.forename: David W
authors.initials: DW
authors.lastname: Miller
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143;
authors.forename: Debajyoti
authors.initials: D
authors.lastname: Datta
authors.affiliation: 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;
authors.forename: Fang
authors.initials: F
authors.lastname: Wu
authors.affiliation: 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;
authors.forename: Chun-Xiang
authors.initials: CX
authors.lastname: Wu
authors.affiliation: 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;
authors.forename: Anuradha
authors.initials: A
authors.lastname: Landeru
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143;
authors.forename: James A
authors.initials: JA
authors.lastname: Wells
authors.affiliation: Laboratory of Neurogenetics, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Mark R
authors.initials: MR
authors.lastname: Cookson
authors.affiliation: Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Boxer
authors.affiliation: Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Thomas
authors.affiliation: Department of Human Physiology, Center for Neuroscience, Flinders University, Adelaide 5001, Australia;
authors.forename: Wei Ping
authors.initials: WP
authors.lastname: Gai
authors.affiliation: 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;
authors.forename: Dagmar
authors.initials: D
authors.lastname: Ringe
authors.affiliation: 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.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Petsko
authors.affiliation: 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.
authors.forename: Quyen Q
authors.initials: QQ
authors.lastname: Hoang
mesh_terms: D000534:Alum Compounds / Q000494:pharmacology; D020170:Caspase 1 / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D016631:Lewy Bodies / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009550:Nigericin / Q000494:pharmacology; D066329:Protein Aggregates / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D024483:Vitamin K 3 / Q000494:pharmacology; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D062366:para-Aminobenzoates / Q000494:pharmacology
chemical_list: D000534:Alum Compounds; D004151:Dipeptides; C508585:IL1B protein, human; D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D066329:Protein Aggregates; D034741:RNA, Small Interfering; C497604:SNCA protein, human; D051844:alpha-Synuclein; D062366:para-Aminobenzoates; C520022:belnacasan; C041524:aluminum sulfate; D024483:Vitamin K 3; D020170:Caspase 1; D009550:Nigericin
keywords: Parkinson's disease; aggregation; caspase; inflammasome; synuclein