Caspase-8 is an effector in apoptotic death of dopaminergic neurons in Parkinson's disease, but pathway inhibition results in neuronal necrosis

Caspase-8 is a proximal effector protein of the tumor necrosis factor recep tor family death pathway. In the present human postmortem study, we observe d a significantly higher percentage of dopaminergic (DA) substantia nigra p ars compacta neurons that displayed caspase-8 activation in Parkinson's dis ease (PD) patients compared with controls. In an in vivo experimental PD mo del, 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 effec t is related to ATP depletion and suggest that the use of caspase inhibitor s in pathologies linked to intracellular energy depletion, such as PD, shou ld be cautiously evaluated.