Proteolytic Cleavage of Extracellular α-Synuclein by Plasmin

Abstract

Background: A prion-like spread of α-synuclein might play a role in the pathogenesis of Parkinson disease., Results: Extracellular α-synuclein was cleaved by plasmin. Cultured microglia and astrocytes did not take up plasmin digested extracellular α-synuclein, and were not activated., Conclusion: Plasmin-mediated α-synuclein clearance problems might play a role in the pathogenesis of Parkinson disease., Significance: Therapies aimed at α-synuclein clearance may lead to new therapies for Parkinson disease., Parkinson disease ({PD)} is the second most common neurodegenerative disease characterized by a progressive dopaminergic neuronal loss in association with Lewy body inclusions. Gathering evidence indicates that α-synuclein (α-syn), a major component of the Lewy body, plays an important role in the pathogenesis of {PD.} Although α-syn is considered to be a cytoplasmic protein, it has been detected in extracellular biological fluids, including human cerebrospinal fluid and blood plasma of healthy and diseased individuals. In addition, a prion-like spread of α-syn aggregates has been recently proposed to contribute to the propagation of Lewy bodies throughout the nervous system during progression of {PD}, suggesting that the metabolism of extracellular α-syn might play a key role in the pathogenesis of {PD.} In the present study, we found that plasmin cleaved and degraded extracellular α-syn specifically in a dose- and time- dependent manner. Aggregated forms of α-syn as well as monomeric α-syn were also cleaved by plasmin. Plasmin cleaved mainly the N-terminal region of α-syn and also inhibited the translocation of extracellular α-syn into the neighboring cells in addition to the activation of microglia and astrocytes by extracellular α-syn. Further, extracellular α-syn regulated the plasmin system through up-regulation of plasminogen activator inhibitor-1 ({PAI-1)} expression. These findings help to understand the molecular mechanism of {PD} and develop new therapeutic targets for {PD.}