Alpha-synuclein activates microglia by inducing the expressions of matrix metalloproteinases and the subsequent activation of protease-activated receptor-1.

Abstract

The mutation or overexpression of alpha-synuclein protein plays a pivotal role in the pathogenesis of Parkinson's disease. In our preliminary experiments, we found that alpha-synuclein induced the expression of matrix metalloproteinases (MMPs) (MMP-1, -3, -8, and -9) in rat primary cultured microglia. Thus, the current study was undertaken to determine the roles of MMPs in alpha-synuclein-induced microglial activation. The inhibition of MMP-3, -8, or -9 significantly reduced NO and reactive oxygen species levels and suppressed the expression of TNF-alpha and IL-1beta. Notably, MMP-8 inhibitor suppressed TNF-alpha production more efficaciously than MMP-3 or MMP-9 inhibitors. Inhibition of MMP-3 or -9 also suppressed the activities of MAPK, NF-kappaB, and AP-1. Previously, protease-activated receptor-1 (PAR-1) has been associated with the actions of MMPs, and thus, we further investigated the role of PAR-1 in alpha-synuclein-induced inflammatory reactions. A PAR-1-specific inhibitor and a PAR-1 antagonist significantly suppressed cytokine levels, and NO and reactive oxygen species production in alpha-synuclein-treated microglia. Subsequent PAR-1 cleavage assay revealed that MMP-3, -8, and -9, but not alpha-synuclein, cleaved the synthetic peptide containing conventional PAR-1 cleavage sites. These results suggest that MMPs secreted by alpha-synuclein-stimulated microglia activate PAR-1 and amplify microglial inflammatory signals in an autocrine or paracrine manner. Furthermore, our findings suggest that modulation of the activities of MMPs and/or PAR-1 may provide a new therapeutic strategy for Parkinson's disease.

• Authors: Eun-Jung Lee, Moon-Sook Woo, Pyong-Gon Moon, Moon-Chang Baek, In-Young Choi, Won-Ki Kim, Eunsung Junn, Hee-Sun Kim
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 185 Issue 1 Pg. 615-23 (Jul 01 2010) ISSN: 1550-6606 [Electronic] United States
• PMID: 20511551 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Inflammation Mediators
• Lipopolysaccharides
• Matrix Metalloproteinase Inhibitors
• Receptor, PAR-1
• Snca protein, rat
• alpha-Synuclein
• Matrix Metalloproteinases

Topics

• Amino Acid Sequence
• Animals
• Autocrine Communication (immunology)
• Cell Line, Tumor
• Cells, Cultured
• Gene Expression Regulation (immunology)
• Humans
• Inflammation Mediators (metabolism, physiology)
• Lipopolysaccharides (physiology)
• Matrix Metalloproteinase Inhibitors
• Matrix Metalloproteinases (biosynthesis, metabolism)
• Microglia (enzymology, metabolism, pathology)
• Molecular Sequence Data
• Paracrine Communication (immunology)
• Protein Processing, Post-Translational (immunology)
• Rats
• Rats, Sprague-Dawley
• Receptor, PAR-1 (agonists, metabolism, physiology)
• alpha-Synuclein (physiology)