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

• Published in: Cellular and molecular life sciences : CMLS Vol. 62; no. 2; pp. 227 - 238
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Switzerland Springer Nature B.V 01-01-2005
• Subjects: 1-Methyl-4-phenylpyridinium - toxicity; Animals; Apoptosis; Apoptosis Inducing Factor; Caspase 2; Caspase 3; Caspase 6; Caspase 7; Caspase 8; Caspase 9; Caspases - metabolism; Cell death; Cell Line; Cytochromes c - biosynthesis; Dopamine - metabolism; Enzyme Activation; Enzymes; Flavoproteins - metabolism; Membrane Proteins - metabolism; Mice; Mitochondria - metabolism; Mortality; Neurons; Neurons - cytology; Neurons - drug effects; Neurons - enzymology; Neurotoxins; Neurotransmitters; Parkinson's disease
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-004-4413-4

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 upstream 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.