Compensatory caspase activation in MPP+-induced cell death in dopaminergic neurons.
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.
Chee
J L Y
JL
Department of Biological Sciences, Faculty of Science, National University of Singapore, 14 Science Drive 4, 117542, Singapore.
Guan
X L
XL
Lee
J Y
JY
Dong
B
B
Leong
S M
SM
Ong
E H
EH
Liou
A K F
AK
Lim
T M
TM
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity; D000818:Animals; D017209:Apoptosis; D051033:Apoptosis Inducing Factor; D053143:Caspase 2; D053148:Caspase 3; D053178:Caspase 6; D053179:Caspase 7; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D045304:Cytochromes c / Q000096:biosynthesis; D004298:Dopamine / Q000378:metabolism*; D004789:Enzyme Activation; D005420:Flavoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*
D051033:Apoptosis Inducing Factor; D005420:Flavoproteins; D008565:Membrane Proteins; C494830:AIFM1 protein, mouse; D045304:Cytochromes c; C505409:Casp3 protein, mouse; C505516:Casp6 protein, mouse; C505524:Casp7 protein, mouse; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053143:Caspase 2; D053148:Caspase 3; D053178:Caspase 6; D053179:Caspase 7; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine