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 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.
Institut National de la Santé et de la Recherche Médicale U289, Hôpital de la Salpêtière, 75013 Paris, France.
A
A
Hartmann
J D
JD
Troadec
S
S
Hunot
K
K
Kikly
B A
BA
Faucheux
A
A
Mouatt-Prigent
M
M
Ruberg
Y
Y
Agid
E C
EC
Hirsch
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000502:physiology*; D004295:Dihydroxyphenylalanine / Q000502:physiology; D004195:Disease Models, Animal; D006801:Humans; D008125:Locus Coeruleus / Q000187:drug effects; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000502:physiology*; D010300:Parkinson Disease / Q000503:physiopathology*; D051381:Rats; D013378:Substantia Nigra / Q000187:drug effects / Q000503:physiopathology*
D004295:Dihydroxyphenylalanine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505526:Casp8 protein, mouse; C505528:Casp8 protein, rat; C506434:Casp9 protein, mouse; C506435:Casp9 protein, rat; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases