Proteolytic cleavage of extracellular ?-synuclein by plasmin: implications for Parkinson disease.

ABSTRACT: 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 ?-synuclein (?-syn), a major component of the Lewy body, plays an important role in the pathogenesis of PD. Although ?-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 ?-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 ?-syn might play a key role in the pathogenesis of PD. In the present study, we found that plasmin cleaved and degraded extracellular ?-syn specifically in a dose- and time- dependent manner. Aggregated forms of ?-syn as well as monomeric ?-syn were also cleaved by plasmin. Plasmin cleaved mainly the N-terminal region of ?-syn and also inhibited the translocation of extracellular ?-syn into the neighboring cells in addition to the activation of microglia and astrocytes by extracellular ?-syn. Further, extracellular ?-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.

SUBMITTER: Kim KS 

PROVIDER: S-EPMC3408156 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature