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The Journal of Neuroscience, March 1, 2002, 22(5):1738-1751
Caspase-3-Dependent Proteolytic Cleavage of Protein Kinase C
Is Essential for Oxidative Stress-Mediated Dopaminergic Cell Death
after Exposure to Methylcyclopentadienyl Manganese Tricarbonyl
Vellareddy
Anantharam,
Masashi
Kitazawa,
Jarrad
Wagner,
Siddharth
Kaul, and
Anumantha G.
Kanthasamy
Parkinson Disorders Research Program, Department of Biomedical
Sciences, Iowa Sate University, Ames, Iowa 50011
In the present study, we characterized oxidative
stress-dependent cellular events in dopaminergic cells after exposure
to an organic form of manganese compound, methylcyclopentadienyl manganese tricarbonyl (MMT). In pheochromocytoma cells, MMT
exposure resulted in rapid increase in generation of reactive oxygen
species (ROS) within 5-15 min, followed by release of mitochondrial
cytochrome C into cytoplasm and subsequent activation of cysteine
proteases, caspase-9 (twofold to threefold) and caspase-3 (15- to
25-fold), but not caspase-8, in a time- and dose-dependent manner.
Interestingly, we also found that MMT exposure induces a time- and
dose-dependent proteolytic cleavage of native protein kinase C
(PKC, 72-74 kDa) to yield 41 kDa catalytically active and 38 kDa
regulatory fragments. Pretreatment with caspase inhibitors (Z-DEVD-FMK
or Z-VAD-FMK) blocked MMT-induced proteolytic cleavage of PKC,
indicating that cleavage is mediated by caspase-3. Furthermore,
inhibition of PKC activity with a specific inhibitor, rottlerin,
significantly inhibited caspase-3 activation in a dose-dependent manner
along with a reduction in PKC cleavage products, indicating a
possible positive feedback activation of caspase-3 activity by PKC.
The presence of such a positive feedback loop was also confirmed by delivering the catalytically active PKC fragment. Attenuation of ROS
generation, caspase-3 activation, and PKC activity before MMT
treatment almost completely suppressed DNA fragmentation. Additionally,
overexpression of catalytically inactive PKCK376R
(dominant-negative mutant) prevented MMT-induced apoptosis in immortalized mesencephalic dopaminergic cells. For the first time, these data demonstrate that caspase-3-dependent proteolytic activation of PKC plays a key role in oxidative stress-mediated apoptosis in
dopaminergic cells after exposure to an environmental neurotoxic agent.
Key words:
apoptosis; oxidative stress; Parkinson's disease; environmental factors; manganese; dopaminergic degeneration
Copyright © 2002 Society for Neuroscience 0270-6474/02/2251738-14$05.00/0
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