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

Authors

  • Dong Hee Choi,

    1. Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea
    2. Institute for Neurochemistry, University of Ulsan College of Medicine, Seoul, Korea
    Search for more papers by this author
  • Eun-Mee Kim,

    1. Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea
    2. Institute for Neurochemistry, University of Ulsan College of Medicine, Seoul, Korea
    Search for more papers by this author
  • Hyo Jin Son,

    1. Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea
    2. Institute for Neurochemistry, University of Ulsan College of Medicine, Seoul, Korea
    Search for more papers by this author
  • Tong H. Joh,

    1. Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, USA
    Search for more papers by this author
  • Yoon Seong Kim,

    1. Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, USA
    Search for more papers by this author
  • Donghou Kim,

    1. Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Korea
    2. Brain Research Center, Asan Institute for Life Science, Seoul, Korea
    Search for more papers by this author
  • M. Flint Beal,

    1. Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, USA
    Search for more papers by this author
  • Onyou Hwang

    1. Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea
    2. Institute for Neurochemistry, University of Ulsan College of Medicine, Seoul, Korea
    3. Brain Research Center, Asan Institute for Life Science, Seoul, Korea
    Search for more papers by this author

Address correspondence and reprint requests to Onyou Hwang, PhD, Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Seoul 138-736, Korea. E-mail: oyhwang@amc.seoul.kr

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.

Ancillary