Mechanisms to prevent caspase activation in rotenone-induced dopaminergic neurodegeneration: role of ATP depletion and procaspase-9 degradation |
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Authors: | HeeWon Kang Baek-Soo Han Su-Jeong Kim Young J Oh |
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Institution: | (1) Department of Biology, Yonsei University College of Life Science and Biotechnology, Seoul, 120-749, Korea;(2) Brain Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 305-806, Korea; |
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Abstract: | The evidence implicating a mode of cell death that either favors or argues against caspase-dependent apoptosis is available
in studies that used experimental models of Parkinson’s disease. We sought to investigate the mechanisms by which release
of cytochrome c is not linked to caspase activation during rotenone-induced dopaminergic (DA) neurodegeneration. Unlike caspase activation
in 6-hydroxydopamine-treated cells, both MN9D DA neuronal cells and primary cultures of mesencephalic neurons showed no obvious
signs of caspase activation upon exposure to rotenone. We found that intracellular levels of ATP significantly decreased at
the early phase of neurodegeneration (<~24 h) and therefore external addition of ATP to the lysates obtained at this stage
reconstituted caspase-3 activity. At a later phase of cell death (>~24 h), both decreased levels of ATP and procaspase-9 contributed
to the lack of caspase-3 activation. Under this condition, calpain and the proteasome system were responsible for the degradation
of procaspase-9. Consequently, external addition of ATP and procaspase-9 to the lysates harvested at the later phase was required
for activation of caspase-3. Similarly, caspase-3 activity was also reconstituted in the lysates harvested from cells co-treated
with inhibitors of these proteases and incubated in the presence of external ATP. Taken together, our findings provided a
sequential mechanism underlying how DA neurons may undergo caspase-independent cell death, even in the presence of cytoplasmic
cytochrome c following inhibition of mitochondrial complex I. |
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