RT Journal Article
SR Electronic
T1 Caspase-8 Is an Effector in Apoptotic Death of Dopaminergic Neurons in Parkinson's Disease, But Pathway Inhibition Results in Neuronal Necrosis
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 2247
OP 2255
DO 10.1523/JNEUROSCI.21-07-02247.2001
VO 21
IS 7
A1 Andreas Hartmann
A1 Jean-Denis Troadec
A1 Stéphane Hunot
A1 Kristy Kikly
A1 Baptiste A. Faucheux
A1 Annick Mouatt-Prigent
A1 Merle Ruberg
A1 Yves Agid
A1 Etienne C. Hirsch
YR 2001
UL http://www.jneurosci.org/content/21/7/2247.abstract
AB 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-tetrahydropyridine-treated 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.