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

J Biol Chem. 2012 Jul 20;287(30):24862-72. doi: 10.1074/jbc.M112.348128. Epub 2012 May 22.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / metabolism*
  • Astrocytes / pathology
  • Cell Line
  • Fibrinolysin / genetics
  • Fibrinolysin / metabolism*
  • Humans
  • Lewy Bodies / genetics
  • Lewy Bodies / metabolism
  • Lewy Bodies / pathology
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neuroglia / metabolism*
  • Neuroglia / pathology
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism*
  • Parkinson Disease / pathology
  • Plasminogen Activator Inhibitor 1 / biosynthesis
  • Plasminogen Activator Inhibitor 1 / genetics
  • Proteolysis*
  • Rats
  • Rats, Sprague-Dawley
  • Up-Regulation / genetics
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism*


  • Nerve Tissue Proteins
  • Plasminogen Activator Inhibitor 1
  • SERPINE1 protein, human
  • alpha-Synuclein
  • Fibrinolysin