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