MODULATION OF CONTROL MECHANISMS OF DOPAMINE-INDUCED APOPTOSIS - A FUTURE APPROACH TO THE TREATMENT OF PARKINSONS-DISEASE

The cause for the progressive and selective degeneration of the dopami nergic (DA) nigrostriatal neurons in Parkinson's disease (PD) is still unknown. We suggest a novel approach, that links this neuronal degene rative process to inappropriate triggering of apoptosis, an active, co ntrolled program of cellular self destruction, by excess oxidative str ess mediated by DA metabolism. In support of this concept, we found th at DA, the endogenous neurotransmitter, is capable of initiating apopt osis in cultured, postmitotic chick sympathetic neurons, an observatio n further extended to other cellular systems (PC-12 cells, cerebellar granular cells, thymocytes, splenocytes). In comparing the relative ap optosis-triggering potency of other mononamine neurotransmitters, DA w as found to be the most active, whereas norepinephrine and serotonin h ad a moderate and a mild effects, respectively. This grading can be co rrelated with the relative involvement of the relevant neuronal system s (i.e., substantia ni,ora, locus ceruleus and raphe nuclei) in PD. We therefore hypothesize that neuronal degeneration in PD may be caused, at least in part, by a failure, either inherited or acquired, in cell ular control systems of apoptosis, that may normally restrain the leth al potential of these endogenous neuro-transmitters and their potentia lly-toxic oxidation products. We therefore point at apoptosis-control, systems as a critical scene of events, where the fate of nigrostriata l neurons is ultimatly determined, and whose modulation may yield atte nuation of the neuronal degenerative process. In support of this conce pt, we found that vector-driven stable expression of the proto-oncogen e bcl-2, an inhibitor of apoptosis, can exert powerful cellular protec tion against DA toxicity in rat pheochromocytoma PC-12 cells. Furtherm ore, cell extracts from bcl-2-expressing cells were found to markedly inhibit in vitro oxidation of DA and production of DA-melanin. We also found that expression of bcl-2 can inhibit the decrease in intracellu lar reduced thiol (-SH) groups which we observed following exposure to DA. Research of the bcl-2 system and associated control mechanisms of apoptosis, possibly acting in association with intra-cellular anti-ox idant pathways, may therefore lead to novel therapeutic approaches for neuroprotection in PPD.