A novel intracellular role of matrix metalloproteinase-3 during apoptosis of dopaminergic cells

J Neurochem. 2008 Jul;106(1):405-15. doi: 10.1111/j.1471-4159.2008.05399.x. Epub 2008 Jul 1.


We have previously demonstrated that the active form of matrix metalloproteinase-3 (actMMP-3) is released from dopamine(DA)rgic neurons undergoing apoptosis. Herein, whether actMMP-3 might be generated intracellularly, and if so, whether it is involved in apoptosis of DArgic neurons itself was investigated in primary cultured DArgic neurons of wild-type, MMP-3 knockout animals, and CATH.a cells. During apoptosis, gene expression of MMP-3 is induced, specifically among the various classes of MMPs, generating the proform (55 kDa) which is subsequently cleaved to the catalytically active actMMP-3 (48 kDa) involving a serine protease. Intracellular actMMP-3 activity is directly linked to apoptotic signaling in DArgic cells: (i) Pharmacologic inhibition of enzymatic activity, repression of gene expression by siRNA, and gene deficiency all lead to protection; (ii) pharmacologic inhibition causes attenuation of DNA fragmentation and caspase 3 activation, the indices of apoptosis; and (iii) inhibition of the pro-apoptotic enzyme c-Jun N-terminal protein kinase leads to repression of MMP-3 induction. Under the cell stress condition, MMP-3 is released as actMMP-3 rather than the proform (proMMP-3), and catalytically active MMP-3 added to the medium does not cause cell death. Thus, actMMP-3 seems to have a novel intracellular role in apoptotic DArgic cells and this finding provides an insight into the pathogenesis of Parkinson's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics*
  • Catalytic Domain / genetics
  • Cell Line
  • Cells, Cultured
  • Cytoprotection / drug effects
  • Cytoprotection / genetics
  • Dopamine / metabolism*
  • Enzyme Activation / genetics
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Enzymologic / genetics
  • Intracellular Fluid / enzymology*
  • Matrix Metalloproteinase 3 / genetics*
  • Mice
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 8 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 8 / metabolism
  • Nerve Degeneration / enzymology
  • Nerve Degeneration / genetics
  • Nerve Degeneration / physiopathology
  • Neurons / drug effects
  • Neurons / enzymology*
  • Neurons / pathology
  • Parkinson Disease / enzymology
  • Parkinson Disease / genetics
  • Parkinson Disease / physiopathology
  • RNA Interference / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Serine Endopeptidases / metabolism
  • Substantia Nigra / enzymology
  • Substantia Nigra / pathology
  • Substantia Nigra / physiopathology


  • Enzyme Inhibitors
  • Mitogen-Activated Protein Kinase 8
  • Serine Endopeptidases
  • Matrix Metalloproteinase 3
  • Dopamine