A novel intracellular role of matrix metalloproteinase-3 during apoptosis of dopaminergic cells |
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Authors: | Choi Dong Hee Kim Eun-Mee Son Hyo Jin Joh Tong H Kim Yoon Seong Kim Donghou Flint Beal M Hwang Onyou |
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Institution: | Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea; Institute for Neurochemistry, University of Ulsan College of Medicine, Seoul, Korea; Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, USA; Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Korea; Brain Research Center, Asan Institute for Life Science, Seoul, Korea |
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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. |
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Keywords: | apoptotic signaling dopaminergic neuron matrix metalloproteinase-3 Parkinson's disease tetrahydrobiopterin |
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