Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 34, Pages 9587-9592Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1610099113
Keywords
synuclein; Parkinson's disease; caspase; inflammasome; aggregation
Categories
Funding
- Community Fast Track grant from Michael J. Fox Foundation
- National Institutes of Health Grants [1R21NS079881-01, 5R01GM111639]
- Indiana University School of Medicine Biomedical Research Grant
- Indiana University-Purdue University Indianapolis Research Support Funds Grant
- Fidelity Biosciences Research Initiative
- Ellison Medical Foundation
- McKnight Endowment for Neuroscience
- Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research
- Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health
- Intramural Research Program of the National Institute on Aging, National Institutes of Health
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The aggregation of alpha-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.
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