[Neuronal death caused by apoptosis in Parkinson disease].
The identity of the neuronal populations (dopaminergic, noradrenergic, serotoninergic, cholinergic) that die in Parkinson's disease is well established. The cause of this degeneration, and the mechanism by which it takes place is still unknown, although there is data, at least for the dopaminergic neurons, suggesting that oxidative stress might play a role. In addition, recent ultrastructural studies of dopaminergic neurons in patients with Parkinson's disease have shown that these neurons die by apoptosis, and immunocytochemical studies have shown that the cytokine TNF-alpha, observed in microglial cells in the substantia nigra of patients post-mortem, might play a role, as might the transcription factor NF-kappa B, which is translocated into the nucleus of dopaminergic neurons in patients, a sign of its activation. We have developed an in vitro model of dopaminergic cell death that accounts for these observations. In both differentiated PC12 cells and primary cultures of mesencephalic neurons, we have shown that when the sphingomyelin-dependent signaling pathway is activated, these cells die by apoptosis, preceded by the production of superoxide radicals in the mitochondria and the nuclear translocation of NF-kappa B. TNF-alpha is known to induce all three such events: apoptosis, activation of the sphingomyelin pathway, free radical production. Our results suggest that the superoxide radicals are used as signalling molecules within the sphingomyelin pathway. These observations may help to explain the origin of the evidence, in postmortem brain from parkinsonian patients, for oxidative stress, hypothesized to be an etiological factor in this disease.
INSERM U.289, Hôpital de la Salpêtrière, Paris.
M
M
Ruberg
V
V
France-Lanord
B
B
Brugg
N
N
Lambeng
P P
PP
Michel
P
P
Anglade
S
S
Hunot
P
P
Damier
B
B
Faucheux
E
E
Hirsch
Y
Y
Agid
D017209:Apoptosis / Q000502:physiology*; D005609:Free Radicals; D006801:Humans; D009474:Neurons / Q000502:physiology*; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000473:pathology* / Q000503:physiopathology
D005609:Free Radicals