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

Dong Hee Choi, Eun Mee Kim, Hyo Jin Son, Tong H. Joh, Yoon Seong Kim, Donghou Kim, M. Flint Beal, Onyou Hwang

Research output: Contribution to journalArticlepeer-review

95 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)405-415
Number of pages11
JournalJournal of neurochemistry
Volume106
Issue number1
DOIs
StatePublished - Jul 2008
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cellular and Molecular Neuroscience

Keywords

  • Apoptotic signaling
  • Dopaminergic neuron
  • Matrix metalloproteinase-3
  • Parkinson's disease
  • Tetrahydrobiopterin

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