NEURONAL DEATH DUE TO APOPTOSIS IN PARKINSONS-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 whic h it takes place is still unknown, although there is data, at least fo r the dopaminergic neurons, suggesting that oxidative stress might pla y a role. In addition, recent ultrastructural studies of dopaminergic neurons in patients with Parkinson's disease have shown that these neu rons die by apoptosis, and immunocytochemical studies have shown that the cytokine TNF-alpha:, observed in microglial cells in the substanti a nigra of patients post-mortem, might play a role, as might the trans cription factor NF-kappa B, which is translocated into the nucleus of dopaminergic neurons in patients, a sign of its activation. We have de veloped an in vitro model of dopaminergic cell death that accounts for these observations. In both differentiated PC12 cells and primary cul tures of mesencephalic neurons, we have shown that when the sphingomye lin-dependent signalling pathway is activated, these cells die by apop tosis, preceded by the production of superoxide radicals in the mitoch ondria and the nuclear translocation of NF-kappa B. TNF-alpha is known to induce all three such events: apoptosis, activation of the sphingo myelin pathway, free radical production. Our results suggest that the superoxide radicals are used as signalling molecules within the sphing omyelin pathway. These observations may help to explain the origin of the evidence, in postmortem brain from parkinsonian patients, for oxyd ative stress, hypothesized to be an etiological factor in this disease .