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

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.