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The Journal of Neuroscience, June 15, 2003, 23(12):5069-5078

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Caspase-Dependent and -Independent Cell Death Pathways in Primary Cultures of Mesencephalic Dopaminergic Neurons after Neurotoxin Treatment

Baek S. Han,¹ Hyun-Seung Hong,¹ Won-Seok Choi,¹ George J. Markelonis,² Tae H. Oh,² and Young J. Oh¹

¹Department of Biology, Yonsei University College of Science, Seoul 120-749, Korea, and ²Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21205

Although the cause of neuronal death in Parkinson's disease (PD) is mainly unknown, growing evidence suggests that both apoptotic and non-apoptotic death may occur in PD. Using primary cultures of mesencephalic dopaminergic neurons and the MN9D dopaminergic neuronal cell line, we attempted to evaluate specifically the existence of the mitochondrial apoptotic pathway, focusing on the mitochondrial release of cytochrome c to the activation of the caspases after 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenylpyridinium (MPP⁺) treatment. Both immunofluorescent labeling and immunoblot analysis indicated mitochondrial release of cytochrome c into the cytosol after 6-OHDA or MPP⁺ treatment. However, the appearance of activated caspase-3 immunoreactivity in tyrosine hydroxylase (TH)-positive neurons was detected only after 6-OHDA. Immunoblot and biochemical analysis also confirmed that activation of both caspase-9 and caspase-3 was induced by 6-OHDA, but not by MPP⁺. Consequently, cotreatment with a caspase inhibitor (zVAD-fmk) or with an antioxidant (N-acetylcysteine) not only deterred 6-OHDA-induced loss of TH-positive neurons but also abolished the appearance of activated caspase-3 in TH-positive neurons. In contrast, the same treatment did not spare MPP⁺-treated TH-positive neurons. Interestingly, a reconstitution assay indicated that the addition of ATP to the cytosolic fraction obtained from MPP⁺-treated cells was sufficient to activate both caspase-9 and caspase-3. Taken together, our results indicate that distinct mechanisms underlie neurotoxin-induced cell death. They also suggest that, after mitochondrial release of cytochrome c in dopaminergic neurons after neurotoxin treatment, intracellular levels of ATP may constitute a critical factor in determining whether a neuron will die by a caspase-dependent or -independent pathway.

Key words: cytochrome c; caspase; 6-hydroxydopamine; MPP⁺; dopaminergic neuron; ATP

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Received Feb. 11, 2003; revised Apr. 4, 2003; accepted Apr. 7, 2003.

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