A novel intracellular role of matrix metalloproteinase-3 during apoptosis of dopaminergic cells
Article first published online: 5 APR 2008
© 2008 The Authors. Journal Compilation © 2008 International Society for Neurochemistry
Journal of Neurochemistry
Volume 106, Issue 1, pages 405–415, July 2008
How to Cite
Choi, D. H., Kim, E.-M., Son, H. J., Joh, T. H., Kim, Y. S., Kim, D., Flint Beal, M. and Hwang, O. (2008), A novel intracellular role of matrix metalloproteinase-3 during apoptosis of dopaminergic cells. Journal of Neurochemistry, 106: 405–415. doi: 10.1111/j.1471-4159.2008.05399.x
- Issue published online: 5 APR 2008
- Article first published online: 5 APR 2008
- Received January 10, 2008; revised manuscript received February 18, 2008; accepted March 28, 2008.
- apoptotic signaling;
- dopaminergic neuron;
- matrix metalloproteinase-3;
- Parkinson’s disease;
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.