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

Authors
Kim, KS; Choi, YR; Park, JY; Lee, JH; Kim, DK; Lee, SJ; Paik, SR; Jou, I; Park, SM
Citation
The Journal of biological chemistry, 287(30):24862-24872, 2012
Journal Title
The Journal of biological chemistry
ISSN
0021-92581083-351X
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 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.
MeSH terms
AnimalsAstrocytes/*metabolism/pathologyCell LineFibrinolysin/genetics/*metabolismHumansLewy Bodies/genetics/metabolism/pathologyNerve Tissue Proteins/genetics/*metabolismNeuroglia/*metabolism/pathologyParkinson Disease/genetics/*metabolism/pathologyPlasminogen Activator Inhibitor 1/biosynthesis/genetics*ProteolysisRatsRats, Sprague-DawleyUp-Regulation/geneticsalpha-Synuclein/genetics/*metabolism
DOI
10.1074/jbc.M112.348128
PMID
22619171
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
AJOU Authors
김, 광수주, 일로박, 상면
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