Caspase-8 Is an Effector in Apoptotic Death of Dopaminergic Neurons in Parkinson's Disease, But Pathway Inhibition Results in Neuronal Necrosis

Abstract

Caspase-8 is a proximal effector protein of the tumor necrosis factor receptor family death pathway. In the present human postmortem study, we observed a significantly higher percentage of dopaminergic (DA) substantia nigra pars compacta neurons that displayed caspase-8 activation in Parkinson's disease (PD) patients compared with controls. In an in vivo experimental PD model, namely subchronically 1,2,3,6-tetrahydropyridinetreated mice, we also show that caspase-8 is indeed activated after exposure to this toxin early in the course of cell demise, suggesting that caspase-8 activation precedes and is not the consequence of cell death. However, cotreatment of 1-methyl-4-phenylpyridinium-intoxicated primary DA cultures with broad-spectrum and specific caspase-8 inhibitors did not result in neuroprotection but seemed to trigger a switch from apoptosis to necrosis. We propose that this effect is related to ATP depletion and suggest that the use of caspase inhibitors in pathologies linked to intracellular energy depletion, such as PD, should be cautiously evaluated. Key words: Parkinson's disease; caspase-8; apoptosis; necrosis; ATP; MPTPSeveral recent human postmortem studies have suggested that dopaminergic (DA) neurons die by apoptosis in Parkinson's disease (PD) (for review, see . Apoptosis is also observed in in vivo and in vitro models of PD based on the toxicity of 1-methyl-4-phenylpyridinium (MPP ϩ ) and 6-hydroxydopamine for DA neurons (Hartley et al., 1994;Mochizuki et al

Caspase-1 and Caspase-8 Cleave and Inactivate Cellular Parkin

“…This demonstrates, first, an increase in the activation of the pro-interleukin-1␤ converting enzyme (caspase-1) and, second, an increased potential for stimulating the caspase-8 activating TNF-␣ receptors on the dopaminergic neurons. This is corroborated by the increased activity of caspase-1 in substantia nigra from patients with Parkinson's disease as compared with substantia nigra from control patients (37) and by the demonstration of increased levels of activated caspase-8 in dopaminergic neurons of the substantia nigra in patients with Parkinson's disease compared with control patients (38,39). Caspase-8 is also activated in the MPTP mouse model of Parkinson's disease (38,39).…”

Dopamine neuron degeneration induced by MPP+ is independent of CED-4 pathway in Caenorhabditis elegans

“…It has been thought that inhibition of caspase is a potential therapeutic approach for PD. However, data from ours and others suggest that caspase inhibition is not sufficient to rescue dopamine neurons from cell death [1][2][3][4]. Once caspase pathway is inhibited, caspase-dependent cell death pathway may switch to caspase-independent cell death pathway.…”

“…Hitherto, it has not been clearly defined whether the cell death induced by MPP + is apoptotic and/or necrotic. Contradictory results have been obtained from the treatment with different doses of MPP + in different culture systems [1][2][3][4]. This study, therefore, aims at determining the cell death mechanisms underlying MPP + -induced dopamine neuron degeneration in vivo in a living animal model of Caenorhabditis elegans.…”

Restoration of Mitochondrial Dysfunction in 6-Hydroxydopamine Induced Parkinson’s disease: a Complete Review

“…An oxidative mechanism for neuronal apoptosis has been suggested to involve ROS generation, inhibition of mitochondrial complex I activity, and caspase-3 activation, overexpression of mutant SNCA in association with elevated 8-hydroxyguanine, protein carbonyls, lipid peroxidation and 3-nitrotyrosine, consistent with oxidative stress [243][244][245][246][247] ( Figure 2). …”