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Published on: January 7, 2014
Compensatory caspase activation in MPP+-induced cell death in dopaminergic neurons
J L Y Chee1, X L Guan, J Y Lee
1Department of Biological Sciences, Faculty of Science, National University of Singapore, 14 Science Drive 4, 117542, Singapore.
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 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.
Insights
Parkinson's disease cell death may not solely involve the typical mitochondrial pathway. This study reveals alternative caspase pathways are activated in dopaminergic neurons following neurotoxin exposure.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Parkinson's disease (PD) is characterized by dopaminergic neuron loss.
- Apoptosis, particularly the mitochondrial pathway, is a hypothesized mechanism of cell death in PD.
- The neurotoxin MPP+ is used to model PD-induced neurodegeneration.
Purpose of the Study:
- To investigate the specific apoptotic pathways involved in dopaminergic cell death induced by MPP+.
- To determine if the canonical mitochondrial apoptotic pathway is activated in response to MPP+.
- To identify alternative or compensatory cell death mechanisms in dopaminergic neurons.
Main Methods:
- Utilized the mouse dopaminergic cell line MN9D.
- Challenged cells with the neurotoxin MPP+ under serum-free conditions.
- Employed caspase inhibitors and time-course studies to analyze cell death pathways.
- Monitored the translocation of apoptosis-inducing factor.
Main Results:
- Apoptosis was the primary mode of cell death following MPP+ treatment.
- Canonical caspases-3 and -9 were not activated.
- Alternative caspases (caspase-2, -8, -6, and -7) were involved in MPP+-induced cell death.
- Apoptosis-inducing factor translocated from mitochondria.
Conclusions:
- Dopaminergic neurons exhibit alternative apoptotic pathways distinct from the classical mitochondrial route.
- Caspase-2 and -8 activation precede caspase-6 and -7 activation in these alternative pathways.
- These findings offer new insights into the mechanisms of neurodegeneration in Parkinson's disease.
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