Regulation of matrix metalloproteinase-9 and tissue plasminogen activator activity by alpha-synuclein in rat primary glial cells

It is increasingly evident that neuroinflammatory response is involved in the pathogenesis of Parkinson's disease. In this study, we examined whether alpha-synuclein, a major components of Lewy body that has been implicated in the modulation of neuroinflammation, regulates MMP-9 and tPA activity, which plays important roles in neurodegeneration as well as regeneration processes, in cultured rat primary glial cells. Monomeric alpha-synuclein dose-dependently increased MMP-9 but not MMP-2 activity as well as mRNA level from cultured rat primary astrocytes and microglial cells. Maximal stimulation was observed at 50 nM alpha-synuclein. In contrast, the activity of tPA was decreased by alpha-synuclein with only marginal changes in the level of mRNA encoding tPA, if any. Interestingly, same concentration of alpha-synuclein aggregates did not induce MMP-9 activity. Overexpression of alpha-synuclein in rat primary astrocytes similarly increased MMP-9 activity. Treatment of alpha-synuclein increased the phosphorylation of ERK1/2 and the inhibition of ERK1/2 reversed the changes in MMP-9 and tPA activity. These results suggest further functional role of alpha-synuclein via regulation of protease systems through modulation of ERK1/2 activity in brain.