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Compensatory caspase activation in MPP+-induced cell death in dopaminergic neurons

Chee, J.L.Y.
Guan, X.L.
Lee, J.Y.
Dong, B.
Leong, S.M.
Ong, E.H.
Liou, A.K.F.
Lim, T.M.
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Alternative Title
Abstract
Many have hypothesized that cell death in Parkinson's disease is via apoptosis and, specifically, by the mitochondrial-mediated apoptotic pathway. We tested this hypothesis using a mouse dopaminergic cell line of mesencephalic origin, MN9D, challenged with the Parkinsonism-causing neurotoxin MPP + (1-methyl-4-phenylpyridinium ion). Apoptosis was the main mode of cell death when the cells were subjected to MPP+ treatment under serum-free conditions for 24 h. Caspase-3 and caspase-9, however, were not activated, thus indicating the existence of alternate or compensatory cell death pathway(s) in dopaminergic neuronal cells. Using caspase inhibitors, we demonstrated that these pathways involve caspase-2, -8, -6 and -7. A time-course study indicated that activation of caspase-2 and -8 occurred up-stream of caspase-6 and caspase-7. Upon MPP+ challenge, the apoptosis-inducing factor was translocated from the mitochondria into the MN9D cytosol and nucleus. These results suggest the existence of alternative apoptotic pathways in dopaminergic neurons.
Keywords
AIF, Apoptosis, Caspase, Cytochrome c, Dopaminergic neuron, Neurotoxin, Parkinson's disease
Source Title
Cellular and Molecular Life Sciences
Publisher
Series/Report No.
Organizational Units
Organizational Unit
BIOLOGICAL SCIENCES
dept
Organizational Unit
PAEDIATRICS
dept
Organizational Unit
Rights
Date
2005-01
DOI
10.1007/s00018-004-4413-4
Type
Article
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