title: Proteolytic cleavage of extracellular α-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 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.
authors.affiliation: Department of Pharmacology, Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon 442-721, Korea.
authors.forename: Kwang Soo
authors.initials: KS
authors.lastname: Kim
authors.forename: Yu Ree
authors.initials: YR
authors.lastname: Choi
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Park
authors.forename: Jung-Ho
authors.initials: JH
authors.lastname: Lee
authors.forename: Dong Kyu
authors.initials: DK
authors.lastname: Kim
authors.forename: Seung-Jae
authors.initials: SJ
authors.lastname: Lee
authors.forename: Seung R
authors.initials: SR
authors.lastname: Paik
authors.forename: Ilo
authors.initials: I
authors.lastname: Jou
authors.forename: Sang Myun
authors.initials: SM
authors.lastname: Park
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D005341:Fibrinolysin / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016631:Lewy Bodies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis / Q000235:genetics; D059748:Proteolysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000235:genetics; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D009419:Nerve Tissue Proteins; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; D051844:alpha-Synuclein; D005341:Fibrinolysin